4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine

Cat.NO.:A189963 Purity:95%

Product Details of [ 1009033-87-7 ]

CAS No. :	1009033-87-7
Formula :	C₁₇H₂₀BNO₂
M.W :	281.16
SMILES Code :	CC1(C)OB(OC1(C)C)C1=CC=C(C=C1)C1=CC=NC=C1
MDL No. :	MFCD12828171
InChI Key :	PTNMCYWJKRZCDE-UHFFFAOYSA-N
Pubchem ID :	58526497

Safety of [ 1009033-87-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 1009033-87-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	21
Num. arom. heavy atoms	12
Fraction Csp3	0.35
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	86.15
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	31.35 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.46
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.05
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.89
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.9
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.26

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.05
Solubility	0.0248 mg/ml ; 0.0000883 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.8
Solubility	0.0446 mg/ml ; 0.000158 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-6.14
Solubility	0.000205 mg/ml ; 0.000000728 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble

Pharmacokinetics

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) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	Yes
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.56 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12’782’590 molecules and tested on 40 external molecules (r² = 0.94)	2.87

Application In Synthesis of [ 1009033-87-7 ]

* 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.

Downstream synthetic route of [ 1009033-87-7 ]

[ 1009033-87-7 ] Synthesis Path-Downstream 1~30

1
[ 1009033-87-7 ]
[ 16400-50-3 ]
[ 1009033-98-0 ]

References: [1]Organic Letters,2008,vol. 10,p. 941 – 944.

2
[ 39795-60-3 ]
[ 73183-34-3 ]
[ 1009033-87-7 ]

Yield	Reaction Conditions	Operation in experiment
100%		A 100 mL sealed tube was charged with 4-(4-bromophenyl)pyridine (0.9 g, 3.8mmol), bis(pinacolato)diboron (1.17 g, 4.61 mmol), potassium acetate (0.745 g, 7.6mmol) and 1-4 dioxane (10 mL). The reaction mixture was purged with argon for 30mm. Then, Pd(dppf)C12 (0.75 g, 0.05 eq) was added and heated at 100 00 over night.After cooing, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuo to yield crude product, which was purified by combif lash to yield title compound (1.0 g, 100.0percent). LCMS: (M+H) = 282.1

References: [1]Patent: WO2014/202528,2014,A1 .Location in patent: Page/Page column 104.
[2]Organic Letters,2008,vol. 10,p. 941 – 944.

3
[ 1009033-87-7 ]
[ 1228585-13-4 ]
[ 1228585-25-8 ]

Yield	Reaction Conditions	Operation in experiment
61%	With caesium carbonate;palladium diacetate; XPhos; In tetrahydrofuran; for 22h;Inert atmosphere; Reflux;	In a stream of argon, 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)phenyl]pyridine (420 mg), 2,4-bis(5-chlrobiphenyl-3-yl)-6-phenyl-1,3,5-triazine (263 mg), cesium carbonate (485 mg), palladium acetate (5.6 mg) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (23.7 mg) were suspended in tetrahydrofuran (15 mL), and the suspension was refluxed for 22 hours. The reaction mixture was left to stand at room temperature, and then low-boiling ingredients were distilled away under a reduced pressure. Methanol was added to the obtained solid. The solid precipitate was recovered by filtration, and the obtained crude product was purified by silica gel chromatography using a methanol/chloroform (1:100 – 1:50) mixed liquid as a developing solvent to give 232 mg of the target 6-phenyl-2,4-bis[4-(4-pyridyl)-1,1′:3′,1′-terphenyl-5′-yl]-1,3,5-triazine as a white powder (yield: 61%). 1H-NMR (CDCl3) :delta7.49(brt,J=7.1Hz,2H) 7.57(d,J=7.5Hz, 4H), 7.61-7.66(m,7H),7.82-7.86(m,8H),7.94(d,J=8.5Hz,4H),8.10(t,J= 1.7Hz,2H),8.73(dd,J=4.5,1.6Hz,4H),8.84(brdd,J=7.7,1.7Hz,2H), 9.04(d,J=1.7Hz,4H). 13C-NMR(CDCl3) :delta121.5(CH4),126.5(CH2) ,127.1(CH2) ,127.4 (CH4),127.6(CH4),127.9(CH2),128.1(CH4),128.7(CH2),129.0 (CH4),129.1(CH2),130.0(CH2),132.8(CH),136.1(quart.),137.5 (quart.2),137.6(quart.2),140.7(quart.2),141.4(quart.2), 141.6(quart.2),142.6(quart.2),147.8(quart.2),150.4(CH4), 171.8(quart.2),171.9(quart.).

References: [1]Patent: EP2361909,2011,A1 .Location in patent: Page/Page column 22; 23.

4
[ 1009033-87-7 ]
[ 1312478-57-1 ]
[ 1358778-93-4 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 – 1670.

5
[ 1009033-87-7 ]
[ 1268250-67-4 ]
[ 1268250-68-5 ]

Yield	Reaction Conditions	Operation in experiment
58%	With caesium carbonate; XPhos;palladium diacetate; In tetrahydrofuran; for 87h;Inert atmosphere; Reflux;	In a stream of argon, 0.40 g (0.81 mmol) of 2-(3,5-dibromophenyl)-4,6-di-p-tolylpyrimidine, 0.48 g (1.70 mmol) of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)phenyl]-pyridine, 0.55 g (1.70 mmol) of cesium carbonate, 7 mg (0.032 mmol) of palladium acetate and 31 mg (0.065 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were suspended in 20 mL of tetrahydrofuran, and the obtained suspension was heated under reflux for 87 hours. The reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate and the thus-deposited solid was collected by filtration. The thus-obtained crude product was purified by silica gel chromatography using a chloroform/methanol (100:1) mixed solvent as an eluent to give 0.30 g of the target 2-[4,4″-di(4-pyridyl)-1,1′ :3′,1″-terphenyl- 5′-yl]-4,6-di-p-tolylpyrimidine as a white solid (yield: 58%). 1H-NMR(CDCl3):delta2.50(s,6H),7.41(d,J=8.0Hz,4H),7.63(dd,J=4.5, 1.5Hz,4H),7.84(d,J=8.3Hz,4H),7.95(d,J=8.3Hz,4H),8.03(t,J=1.8Hz, 1H),8.05(s,1H),8.24(d,J=8.0Hz,4H),8.73(dd,J=4.5,1.5Hz,4H),9.02(d, J=1.8Hz,2H). 13C-NMR(CDCl3):delta21.6(CH3),31.0(CH3),110.1(CH),121.5(CH×4), 126.7(CH×2),127.3(CH×4),127.5(CH×4),128.2(CH×4),129.7(CH×4),134.7 (quart.×2),137.3(quart.×2),139.9(quart.),141.2(quart.×2),141.3 (quart.×2),142.0(quart.×2),147.9(quart.×2),150.4(CH×4), 164.0(quart.),164.7(quart.×2).

References: [1]Patent: EP2468731,2012,A1 .Location in patent: Page/Page column 37-38.

6
[ 1009033-87-7 ]
[ 1407504-40-8 ]
[ 1383795-51-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 90℃; for 12h;	15.0 g (32.2 mmol) of the intermediate product (N), 10.9 g (38.6 mmol) of <strong>[1009033-87-7]4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine</strong>, and 1.1 g (1.0 mmol) of tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] were dissolved in 300 mL of a tetrahydrofuran (THF) solvent. A solution in which 8.9 g (64.4 mmol) of potassium carbonate (K2CO3) was dissolved in 100 ml of water was added thereto, and they were reacted at 90 C. for 12 hours. The solvent was removed under a reduced pressure, and the reaction product was rinsed with water and methanol. The residues were recrystallized with toluene, precipitated crystals were separated by a filter, rinsed with toluene, and dried to provide a white solid of a compound in 17.0 g (yield: 90%). (calculation value: 584.71, measurement value: MS[M+1] 585.01)

References: [1]Patent: US2012/280613,2012,A1 .Location in patent: Page/Page column 277-278.

7
[ 1009033-87-7 ]
[ 1407504-43-1 ]
[ 1407503-02-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 90℃; for 12h;	20.0 g (23.6 mmol) of the intermediate product (N), 18.1 g (64.4 mmol) of <strong>[1009033-87-7]4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine</strong>, and 1.5 g (1.3 mmol) of tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] were dissolved in 400 ml of a tetrahydrofuran (THF) solvent. A solution in which 11.9 g (85.8 mmol) of potassium carbonate (K2CO3) was dissolved in 200 ml of water was added thereto, and then they were reacted at 90 C. for 12 hours. The solvent was removed under a reduced pressure, and the reaction product was rinsed with water and methanol. The residues were recrystallized with toluene, precipitated crystals were separated by a filter, rinsed with toluene, and dried to provide a white solid of a compound in 16.0 g (yield: 64%). (calculation value: 584.71, measurement value: MS[M+1] 585.01)

References: [1]Patent: US2012/280613,2012,A1 .Location in patent: Page/Page column 283-284.

Yield	Reaction Conditions	Operation in experiment
		General procedure: Step-ii: 1-(2-fluorobenzyl)-4-( 4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole1-(2-fluorobenzyl)-4-iodo-1H-pyrazole (2.25 g, 7.4 mmol) and bispinocalatodiboron (2.07 g,8.2 mmol) were added to a solution of DMSO (20 ml) previously purged with argon (10min). The reaction mixture was purged with argon for a further 15mins, followed by the10 addition of potassium acetate (2.19 g, 22.3 mmol) andbis(triphenylphosphine)palladium(II)dichloride (261 mg, 0.3725 mmol). The resultingmixture was heated to reflux at 80 oc overnight. The reaction was monitored by TLC (40%ethyl acetate in hexane). The reaction mixture was cooled and diluted with ethyl acetate (100ml) and filtered over celite bed and the filtrate was washed with cold water (2×100 ml). The15 organic layer was dried over NazS04, and concentrated under reduced pressure to afford 2.3 gof the crude product which was taken as such for next reaction.

9
[ 1009033-87-7 ]
[ 1450642-87-1 ]
[ 1534378-91-0 ]

Yield	Reaction Conditions	Operation in experiment
70.5%		Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-5 fluorobenzyl)-3,5-dimethyl-1 H-pyrazol-4-yl)-l-tosyl-1H-pyrrolo[2,3-b] pyridine (step-i ofexample-14) (150mg, 0.27mmol) was coupled with <strong>[1009033-87-7]4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine</strong> (intermediate 45) (91.44mh, 0.32mmol) in sodiumcarbonate (85.86, 0.81mmol), toluene/ethanol/water (5/5/2ml). This afforded 120mg (70.5%yield) of the titled compound.

References: [1]Patent: WO2014/6554,2014,A1 .Location in patent: Page/Page column 102.

10
[ 106-37-6 ]
[ 1009033-87-7 ]

References: [1]Patent: WO2014/202528,2014,A1 .

11
[ 1692-15-5 ]
[ 1009033-87-7 ]

References: [1]Patent: WO2014/202528,2014,A1 .

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