156573-09-0|1-Bromo-4-ethoxy-2,3-difluorobenzene| Ambeed

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Quality Control of [ 156573-09-0 ] Purity: 97% SDS Specification

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Product Details of [ 156573-09-0 ]

CAS No. :	156573-09-0
Formula :	C₈H₇BrF₂O
M.W :	237.04
SMILES Code :	CCOC1=C(F)C(F)=C(Br)C=C1
MDL No. :	MFCD07368018
InChI Key :	OJZVBJOHBGYINN-UHFFFAOYSA-N
Pubchem ID :	26985491

Safety of [ 156573-09-0 ]

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

Computational Chemistry of [ 156573-09-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	45.36
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	9.23 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.52
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	3.15
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.97
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.	3.71
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	3.67
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.4

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.53
Solubility	0.0696 mg/ml ; 0.000294 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.	-3.01
Solubility	0.23 mg/ml ; 0.000969 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	-4.35
Solubility	0.0107 mg/ml ; 0.000045 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.51 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	1.0
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)	1.8

Application In Synthesis of [ 156573-09-0 ]

* 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 [ 156573-09-0 ]

[ 156573-09-0 ] Synthesis Path-Downstream 1~35

1
[ 56309-94-5 ]
[ 156573-09-0 ]
[ 954119-09-6 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; magnesium; In tetrahydrofuran;	First Step: 6.1 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 40° C. 59.7 g of <strong>[156573-09-0]1-bromo-4-ethoxy-2,3-difluorobenzene</strong> (1) dissolved in 300 mL of THF was slowly added dropwise thereto at a temperature range of from 40 to 60° C., followed by stirring for 60 minutes. Thereafter, 50.0 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)cyclohexanone (2) dissolved in 150 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 60° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 900 mL of a 3percent ammonium chloride aqueous solution and 500 mL of toluene cooled to 0° C. in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a saturated sodium bicarbonate aqueous solution, and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 100.1 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexanol (3). The resulting compound (3) was a yellow solid.

References: [1]Patent: US2008/63814,2008,A1 .

2
[ 156573-09-0 ]
[ 1740-64-3 ]
[ 1220992-61-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; magnesium; In tetrahydrofuran; water; toluene;	Seventh Step: 1.76 g of well dried magnesium and 10 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 53 C. 17.2 g of the compound (1) dissolved in 30 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 56 C., followed by stirring for 30 minutes. Thereafter, 6.0 g of the compound (16) dissolved in 10 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 55 C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25 C., the reaction mixture was poured into and mixed with a mixture of 100 mL of 1N hydrochloric acid and 100 mL of toluene. The mixture was then separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution, and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 18.5 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-vinylcyclohexanol (17) as a yellow liquid.

References: [1]Patent: US2008/63814,2008,A1 .

Yield	Reaction Conditions	Operation in experiment
		Example 7 Properties of Liquid Crystal Compound (No. 132) A liquid crystal composition (v) including 85% by weight of the base mixtures (i) and 15% by weight of 4-(4-ethoxy-2,3-difluorophenyl)-trans-4'-vinylbicyclohexyl-3-ene (No. 132) obtained in Example 1 was prepared.

4
[ 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.

5
[ 4746-97-8 ]
[ 156573-09-0 ]
[ 220436-96-4 ]

Yield	Reaction Conditions	Operation in experiment
		First Step Magnesium (dried; 6.1 g) and THF (20 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 40 C. 1-Bromo-4-ethoxy-2,3-difluorobenzene (12) (59.2 g) dissolved in THF (300 ml) was slowly added dropwise thereto in the temperature range of 40 C to 60 C, and the stirring was continued for another 60 minutes. Then, 1,4-dioxaspyro[4.5]decane-8-one (13) (30.0 g) dissolved in THF (150 ml) was slowly added dropwise in the temperature range of 50 C to 60 C, and the stirring was continued for another 60 minutes. The obtained reaction mixture was cooled to 30 C, poured into to a vessel containing an aqueous solution of ammonium chloride (3%; 900 ml) and toluene (500 ml) which were cooled to 0 C, and mixed. The mixture obtained was allowed to stand until it had separated into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 86.2 g of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspyro[4.5]decan-8-ol (14).
		Compound (T-2) (142.2 g) obtained in the above step was dissolved in dry tetrahydrofuran (hereinafter, abbreviated as DryTHF) (500 ml), and the resultant solution was cooled to -70C, n-BuLi (364 ml) was added dropwise in a nitrogen atmosphere, and agitation was carried out at -70C for 2 hours. Then, a DryTHF solution of cyclohexanedione monoethylene ketal (T-3) (93.6 g) was slowly added dropwise, the resultant solution was heated to room temperature and agitated for 16 hours. After completion of the reaction, 2N-HCl (200 ml) was added, 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 dissolved in toluene (400 ml), p-TsOH (4.74 g) was added, and heating reflux was carried out for 4 hours while performing dehydration. After completion of the reaction, 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 silica gel column chromatography (heptane:ethyl acetate = 20:1 in a volume ratio) and recrystallization (Solmix), and thus (T-4) was obtained as a colorless crystal (126.1 g, yield: 71%).

References: [1]Patent: EP2266941,2010,A1 .Location in patent: Page/Page column 39.
[2]Patent: EP2484658,2012,A1 .Location in patent: Page/Page column 37.

6
[ 64-67-5 ]
[ 144292-32-0 ]
[ 156573-09-0 ]

References: [1]Synlett,2011,p. 1273 - 1276.

7
[ 156573-09-0 ]
C₂₁H₂₈F₂O [ No CAS ]

References: [1]Synlett,2011,p. 1273 - 1276.

8
[ 156573-09-0 ]
[ 1325238-63-8 ]
C₂₁H₃₀F₂O [ No CAS ]

References: [1]Synlett,2011,p. 1273 - 1276.

9
[ 156573-09-0 ]
[ 1053236-86-4 ]
C₂₁H₃₀F₂O₂ [ No CAS ]

References: [1]Synlett,2011,p. 1273 - 1276.

10
[ 156573-09-0 ]
C₁₅H₂₆O [ No CAS ]
C₂₃H₃₂F₂O [ No CAS ]

References: [1]Synlett,2011,p. 1273 - 1276.

11
[ 156573-09-0 ]
C₁₅H₂₆O [ No CAS ]
C₂₃H₃₄F₂O₂ [ No CAS ]

References: [1]Synlett,2011,p. 1273 - 1276.

12
[ 74-96-4 ]
[ 156573-09-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; tetrabutylammomium bromide; In water;	Preparation of 1-ethoxy-2,3-difluorobromobenzene (T-2) Sodium hydroxide (75.9 g) was added to a water (400 ml) solution of 4-bromo-2,3-difluorophenol (T-1) (195.0 g), bromoethane (196.2 g) and tetrabutylammonium bromide (hereinafter abbreviated as TBAB) (24.2 g), and the mixture was heated at 80 C. for 6 hours with stirring under an atmosphere of nitrogen. After the reaction had been completed, the reaction mixture was extracted with heptane and the organic layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to give a black oil. The oil was purified by distillation to give 1-ethoxy-2,3-difluorobromobenzene (T-2) (230.0 g, 97% yield) as a colorless oil.

References: [1]Patent: US2011/291047,2011,A1 .

13
[ 109-72-8 ]
[ 156573-09-0 ]
[ 84131-68-0 ]
3-butyl-1-(4-ethoxy-2,3-difluorophenyl)cyclopentanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In tetrahydrofuran; hexane;	Second Step THF (40 ml) was added to <strong>[156573-09-0]1-bromo-4-ethoxy-2,3-difluorobenzene</strong> (3.56 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to -78 C. n-Butyllithium (1.65 M, in a hexane solution) (9.1 ml) was added dropwise at a temperature of -70 C. or lower. The stirring was continued at -78 C. for another 1.5 hour and 3-butyl-cyclopentanone (2.1 g) obtained in the first step, in a THF (20 ml) solution was added dropwise at a temperature of -70 C. or lower. After the mixture had been stirred at -78 C. for another 1 hour, it was warmed to room temperature, and a saturated aqueous solution of ammonium chloride (50 ml) was added. The mixture was separated, and the water layer was extracted with diethyl ether three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/9 by volume) to give 3-butyl-1-(4-ethoxy-2,3-difluorophenyl)cyclopentanol (2.8 g).

References: [1]Patent: US2011/309300,2011,A1 .

14
[ 109-72-8 ]
[ 156573-09-0 ]
[ 1352565-97-9 ]
[ 1352566-02-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In tetrahydrofuran; hexane;	First Step THF (100 ml) was added to <strong>[156573-09-0]1-bromo-4-ethoxy-2,3-difluorobenzene</strong> (5.1 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to -78 C. n-Butyllithium (1.57 M, in a hexane solution) (13.8 ml) was added dropwise at a temperature of -70 C. or lower. The stirring was continued at -78 C. for another 2 hours, and 4-(3-propylcyclopentyl)-cyclohexanone (3.0 g) in a THF (10 ml) solution was added dropwise at a temperature of -70 C. or lower. After the mixture had been stirred at -78 C. for another 1 hour, it was warmed to room temperature, and a saturated aqueous solution of ammonium chloride (50 ml) was added. The mixture was separated, and the water layer was extracted with ethyl acetate three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/9 by volume) to give 1-(4-ethoxy-2,3-difluorophenyl)-4-(3-propylcyclopentyl)cyclohexanol (5.0 g).

References: [1]Patent: US2011/309300,2011,A1 .

15
[ 156573-09-0 ]
[ 84131-68-0 ]
[ 1352565-93-5 ]
[ 1352565-94-6 ]

References: [1]Patent: US2011/309300,2011,A1 .

16
[ 156573-09-0 ]
1-ethoxy-2,3-difluoro-4-(4-(3-propylcyclopentyl)cyclohexyl)benzene [ No CAS ]

References: [1]Patent: US2011/309300,2011,A1 .

17
[ 156573-09-0 ]
[ 1352566-03-0 ]

References: [1]Patent: US2011/309300,2011,A1 .

18
[ 156573-09-0 ]
[ 121219-16-7 ]
[ 1241535-57-8 ]