212386-71-5|(4-Ethoxy-2,3-difluorophenyl)boronic acid| Ambeed

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Quality Control of [ 212386-71-5 ] Purity: 97% SDS Specification

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Product Details of [ 212386-71-5 ]

CAS No. :	212386-71-5
Formula :	C₈H₉BF₂O₃
M.W :	201.96
SMILES Code :	FC1=C(F)C(B(O)O)=CC=C1OCC
MDL No. :	MFCD09258743
InChI Key :	OBKSFBWOZSQGGC-UHFFFAOYSA-N
Pubchem ID :	15135235

Safety of [ 212386-71-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 212386-71-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	3
Num. H-bond acceptors	5.0
Num. H-bond donors	2.0
Molar Refractivity	47.48
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.69 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	1.36
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.88
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.	1.18
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	0.46
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.78

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.07
Solubility	1.73 mg/ml ; 0.00855 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.01
Solubility	1.99 mg/ml ; 0.00986 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	-2.38
Solubility	0.832 mg/ml ; 0.00412 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	No
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	No
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	No
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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.57 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<1.0
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)	2.3

Application In Synthesis of [ 212386-71-5 ]

* 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 [ 212386-71-5 ]

[ 212386-71-5 ] Synthesis Path-Downstream 1~35

1
[ 156573-09-0 ]
[ 121-43-7 ]
[ 212386-71-5 ]

Yield	Reaction Conditions	Operation in experiment
71%		According to the synthetic scheme shown above, compound (T-2) (129.5 g) obtained as an intermediate of Example 1 was dissolved in DryTHF (500 ml), and the resultant solution was cooled to -70C. In a nitrogen atmosphere, n-BuLi (500 ml) was added dropwise, and agitation was carried out at -70C for 2 hours. Then, a DryTHF solution of trimethyl borate (129.5 g) was slowly added dropwise at -70C, and the resultant solution was heated to room temperature and agitated for 16 hours. After completion of the reaction, 2N-HCl (200 ml) was added, and then extraction was carried out with toluene, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a light brown solid was obtained. The resultant material was subjected to recrystallization (heptane: toluene = 4 : 1 in a volume ratio), and thus (T-20) was obtained as a colorless crystal (117.2 g, yield: 71%).
71%		The compound (T-2) obtained in the above step(129.5 g) was dissolved in Dry THF (500 ml)It was cooled to -70 C.N-BuLi (500 ml) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at -70 C. for 2 hours. Thereafter, a Dry THF solution of trimethyl borate (129.5 g) was slowly added dropwise at -70 C., the temperature was raised to room temperature, and the mixture was stirred for 16 hours.After completion of the reaction, 2N HCl (200 ml) was added and the mixture was extracted with toluene, washed with water and saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a light brown solid.This product was recrystallized (heptane: toluene = 4: 1 by volume ratio) to obtain (T-20) as colorless crystals (117.2 g, yield 71%).
		In a reactor under nitrogen atmosphere, 50 ml of tetrahydrofuran (THF) was added to 6.15g of magnesium (Mg), followed by stirring at 44 C. 60.0 g of 1-bromo-4-etoxy-2,3-difluorobenzene (a1) dissolved in 130 ml of THF was added dropwise thereto in the temperature range of 38 C. to 49 C. for 1 hour. The resulting solution was added dropwise to a solution of 200 ml of THF and 39.5 g of trimethyl boratein the temperature range of -50 C. to -30 C. The reaction solution was injected into a mixture of 500 ml of 1N hydrochloric acid and 600 ml of ethyl acetate. The mixture was separated into organic layer and aqueous layer, and the organic layer was extracted. The resulting organic layer was washed with saturated chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to provide the residue. The resulting residue was purified by re-crystallization from a heptane, dried to provide 41.6 g of 4-ethoxy-2,3-difluorophenylboronic acid (a2) as a yellew solid.

References: [1]Patent: EP2484658,2012,A1 .Location in patent: Page/Page column 42.
[2]Patent: JP5663957,2015,B2 .Location in patent: Paragraph 0137-0138; 0140.
[3]Patent: US2009/278089,2009,A1 .Location in patent: Page/Page column 13.

2
[ 144292-32-0 ]
[ 212386-71-5 ]
[ 1194726-47-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;palladium on activated charcoal; In isopropyl alcohol; for 10h;Reflux; Inert atmosphere;	In a reactor under nitrogen atmosphere, 20.0 g of compound (a2)17.2 g of 4-bromo-2,3-difluorophenol (a3), 30.6 g of sodium carbonate, 0.54 g of palladium on carbon catalyst (Pd/C) were dissolved in 120 mL of 2-propanol (IPA). After stirring by refluxing for 10 hours, the reaction mixture was cooled to room temperature, and injected into a mixture of 500 ml of 1N hydrochloric acid and 300 ml of toluene which was cooled into 0 C. The mixture was separated into organic layer and aqueous layer and the organic layer was extracted. The resulting organic layer was washed with saturated chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to provide the residue. The resulting residue was purified by recrystallization from heptan, dried to provide 13.2 g of 4'-ethoxy-2,3,2',3'-tetrafluorobiphenyl-4-ol (a4) as a white solid.

References: [1]Patent: US2009/278089,2009,A1 .Location in patent: Page/Page column 13.

3
[ 589-87-7 ]
[ 212386-71-5 ]
[ 470461-09-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In Solmix A-11; water; toluene; for 2h;Inert atmosphere; Reflux;	First Step: 4-Bromoiodobenzene (1) (20.0 g), <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong> (2)(14.4 g), potassium carbonate (29.3 g), Pd(Ph3P)2Cl2 (1.49 g), toluene (100 ml) , Solmix A-11 (100 ml), and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 C, and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from Solmix A-11 and dried, giving 20.8 g of 4-ethoxy-4'-bromo-2,3-difluoro-1,1'-biphenyl (3). The yield based on the compound (1) was 94.0%.
94%	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In Solmix A-11; water; toluene; for 2h;Reflux; Inert atmosphere;	4-Ethoxy-2,3-difluorophenylboronic acid (7) (14.4 g), 4-bromoiodobenzene (8) (20.0 g), potassium carbonate (29.3 g), Pd (Ph3P)2Cl2 (1.49g), toluene (100ml), Solmix A-11 (100ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 C, and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. Then, the solution was concentrated under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel; toluene). The product was further purified by means of recrystallization (Solmix A-11), giving 20.8 g of 4-ethoxy-4'-bromo-2,3-difluoro-1,1'-biphenyl (9). The yield based on the compound (8) was 94.0%.

References: [1]Patent: EP2206695,2010,A1 .Location in patent: Page/Page column 44.
[2]Patent: EP2266941,2010,A1 .Location in patent: Page/Page column 38.

4
[ 1449-68-9 ]
[ 212386-71-5 ]
[ 1123312-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 20h;Reflux;	Method B (from 2-bromoselenophene): A mixture of 45.0 g (0.21 mol) of 2-bromoselenophene, 52.0 g (0.26 mol) of <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong>, 20.0 g (17.3 mmol) of tetrakis(triphenylphosphine)palladium(0) and 600 ml of 2 N sodium carbonate soln. in 1100 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)selenophene is obtained as a beige solid.

References: [1]Patent: US2010/216986,2010,A1 .Location in patent: Page/Page column 36.

5
[ 59163-67-6 ]
[ 212386-71-5 ]
[ 1123312-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 1.5h;Reflux;	Example 30; 2-(4-Ethoxy-2,3-difluorophenyl)-5-propyltellurophene; 30.1 Preparation of 2-(4-ethoxy-2,3-difluorophenyl)tellurophene; A mixture of 10.0 g (38.7 mmol) of 2-bromotellurophene, 8.0 g (39.6 mmol) of <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong>, 3.5 g (3.0 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 100 ml of 2 N sodium carbonate soln. in 200 ml of toluene/ethanol (1:1) is heated under reflux for 1.5 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)tellurophene is obtained as a yellow solid.

References: [1]Patent: US2010/216986,2010,A1 .Location in patent: Page/Page column 59.

6
[ 37686-36-5 ]
[ 212386-71-5 ]
[ 1123312-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 23h;Reflux;	Example 4; 2-(4-Ethoxy-2,3-difluorophenyl)-5-methylselenophene; 4.1 Preparation of 2-(4-ethoxy-2,3-difluorophenyl)selenophene; Method A (from 2-iodoselenophene): A mixture of 34.8 g (0.14 mol) of 2-iodoselenophene, 32.8 g (0.16 mol) of <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong>, 8.10 g (77.01 mmol) of tetrakis -(triphenylphosphine)palladium(0) and 300 ml of 2 N sodium carbonate soln. in 800 ml of toluene/ethanol (1:1) is heated under reflux for 23 h. The mixture is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=15:1-10:1?5:1). Further purification is carried out by recrystallisation from n-heptane; 2-(4-ethoxy-2,3-difluorophenyl)selenophene is obtained as a beige solid.

References: [1]Patent: US2010/216986,2010,A1 .Location in patent: Page/Page column 36.

7
[ 212386-71-5 ]
[ 51934-41-9 ]
[ 1190955-69-1 ]

Yield	Reaction Conditions	Operation in experiment
67.9%	With potassium carbonate;palladium on carbon; In ethanol; water; toluene; for 2h;Reflux; Inert atmosphere;	Ethyl 4-iodoethylbenzoate (1) (25.0 g), <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong> (2) (20.1 g), potassium carbonate (25.0 g), Pd/C (0.25 g), toluene (100 ml), ethanol (100 ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 C, and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases. The extraction to an organic phase was carried out. The organic phase obtained was washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel; toluene). The product was further purified by means of recrystallization from ethanol and dried, giving 18.8 g of ethyl 4-ethoxy-2,3-difluoro-4'-biphenylcarboxylate (3). The yield based on the compound (1) was 67.9%.
67.9%	With potassium carbonate;5% Pd(II)/C(eggshell); In ethanol; water; toluene; for 2h;Inert atmosphere; Reflux;	Example 1; Synthesis of 4-ethoxy-2,3-difluoro-4'-[2,3-difluoro-4-(4-pentylcyclohexyl)phenoxymethyl]-1,1'-biphenyl (No. 1123) [Show Image] First Step: 4-Iodoethyl benzoate (1) (25.0 g), <strong>[212386-71-5]4-ethoxy-2,3-difluorophenylboronic acid</strong> (2) (20.1 g), potassium carbonate (25.0 g), palladium on carbon (NX type of 5%Pd/C; 50% wet; made by N. E. Chemcat; hereinafter referred to as Pd/C) (0.25 g), toluene (100 ml), ethanol (100 ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 C, and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from ethanol and dried, giving 18.8 g of ethyl 4-ethoxy-2,3-difluoro-4'-biphenylbenzoate (3). The yield based on the compound (1) was 67.9%.

References: [1]Patent: EP2266941,2010,A1 .Location in patent: Page/Page column 36.
[2]Patent: EP2305627,2011,A1 .Location in patent: Page/Page column 39.

8
[ 212386-71-5 ]
[ 1190955-71-5 ]