178546-34-4|3-Bromo-5-fluoro-2-hydroxybenzaldehyde| Ambeed

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Quality Control of [ 178546-34-4 ] Purity: 95% SDS Specification

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Product Details of [ 178546-34-4 ]

CAS No. :	178546-34-4
Formula :	C₇H₄BrFO₂
M.W :	219.01
SMILES Code :	OC1=C(C=O)C=C(F)C=C1Br
MDL No. :	MFCD08458073
Boiling Point :	No data available
InChI Key :	LRRWJLDTMGYWFO-UHFFFAOYSA-N
Pubchem ID :	23148955

Safety of [ 178546-34-4 ]

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

Computational Chemistry of [ 178546-34-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	41.51
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.63
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	2.37
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.53
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.	1.97
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	2.6
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.22

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.03
Solubility	0.205 mg/ml ; 0.000936 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.	-2.79
Solubility	0.352 mg/ml ; 0.00161 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	-2.91
Solubility	0.269 mg/ml ; 0.00123 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	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	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.	-5.95 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)	1.4

Application In Synthesis of [ 178546-34-4 ]

* 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 [ 178546-34-4 ]

[ 178546-34-4 ] Synthesis Path-Downstream 1~35

1
[ 347-54-6 ]
[ 178546-34-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 5h;	N-BROMOSUCCINIMIDE (1.51 g, 8.52 mmol) was added to a magnetically stirred solution OF 5-FLUORO-2-HYDROXYBENZALDEHYDE (1 g, 7.1 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 5 hour. The mixture was diluted with ethyl acetate and the organic layer was washed with 5% citric acid, brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product was purified from the residue by chromatography over silica gel employing 50% ethyl acetate/hexanes to give 3-bromo-5-fluoro- 2-hydroxybenzaldehyde (1.2 g)

References: [1]Patent: WO2004/50637,2004,A2 .Location in patent: Page 70.

2
[ 100-97-0 ]
[ 496-69-5 ]
[ 178546-34-4 ]

Yield	Reaction Conditions	Operation in experiment
83%		Hexamethylenetetramine (14.7 g, 105 mmol) was slowly added to a solution of 2-bromo-4-fluoro-phenol (10 g, 52.4 mmol) in trifluoroacetic acid (40 ml) at rt and heated to reflux for 18 h. The reaction mixture was cooled to rt and then water (60 ml) and sulfuric acid (30 ml, 50%) were added. The mixture was stirred for 3 h at rt and then extracted twice with ethyl acetate. The combined organic extracts were washed with 1N HCl, water, dried (Na2SO4), filtered and concentrated under reduced pressure to give 9.5 g (83%) of 3-bromo-5-fluoro-2-hydroxy-benzaldehyde.1H NMR (400 MHz, chloroform-d) delta ppm 9.82 (s, 1H), 7.55-7.62 (m, 1H), 7.21-7.32 (M, 1H).
73%	With trifluoroacetic acid; for 10h;Reflux;	Weigh compound 30-1 (1.02 g, 5.33 mmol) in trifluoroacetic acid (7 mL), Ulotropine (1.5 g, 10.66 mmol) was added in portions. The system was reacted at reflux for 10 h. After the reaction is over, The system was adjusted to pH = 1 with a 1N hydrochloric acid solution, and the aqueous phase was extracted with ethyl acetate (15 mL x 3). Combined organic phases, Wash with saturated saline (10mL x 1), Dried over anhydrous sodium sulfate, The solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100: 1-80: 1), Compound 30-2 was obtained (yellow solid, 739 mg).
	With trifluoroacetic acid; at 80℃;	a) 3-Bromo-5-fluoro-2-hydroxybenzaldehyde A mixture of 2-bromo-4-fluorophenol (5 g, 26.18 mmol), trifluoroacetic acid (60 mL), and hexamethylemetetramine (3.68 g, 26.29 mmol) was stirred overnight at 80 C. The resulting solution was extracted with ethyl acetate (2*20 mL) and the organic layers combined. The resulting mixture was washed with H2O. The resulting mixture was washed with sodium bicarbonate (aq). The resulting residue was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 3-bromo-5-fluoro-2-hydroxybenzaldehyde as a yellow solid.

To a solution of 2-bromo-4-fluorophenol (2g) in trifluoroacetic acid (10mL) was added hexamethylenetetramine (2.94g) at room temperature, and the resulting mixture was stirred under reflux for 20 hours. A 50% aqueous solution of sulfuric acid was added to the reaction mixture, and the mixture was stirred for further 4 hours at room temperature. The reaction mixture was extracted with ethyl acetate, and washed with water, 1mol/L hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound (1.93g). 1H-NMR (CDCl3) delta ppm: 7.25-7.30 (1H, m), 7.56-7.61 (1H, m), 9.83 (1H, s), 11.35 (1H, s)

References: [1]Patent: US2010/331341,2010,A1 .Location in patent: Page/Page column 32.
[2]Patent: CN110627817,2019,A .Location in patent: Paragraph 0383-0386.
[3]Patent: US2014/275172,2014,A1 .Location in patent: Paragraph 0534.
[4]Patent: EP1710233,2006,A1 .Location in patent: Page/Page column 21.

3
[ 178546-34-4 ]
C₇H₄BrFO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;	Intermediate 155 3-Bromo-5-fluoro-benzene-1,2-diol: To a solution of <strong>[178546-34-4]3-bromo-5-fluoro-2-hydroxy-benzaldehyde</strong> (12.04 g, 55 mmol) in methylene chloride (200 mL) was added m-CPBA (77% max, 5.3 g). The resulting mixture was stirred at room temperature overnight and quenched with 10% sodium sulfite and 10% sodium bicarbonate. The mixture was extracted with methylene chloride and washed with water. The solvent was removed under vacuum to afford crude material as a light yellow oil. To a solution of the crude oil in methanol was added sodium hydroxide (8.8 g, 0.22 mol) at room temperature. The mixture was stirred at room temperature overnight and neutralized with concentrated hydrochloric acid. The mixture was extracted with methylene chloride and washed with water. The organic solvent was removed under vacuum. Chromatography with 10-40% ethyl acetate in hexanes afforded 6.8 g (60%) of the title compound as a yellow oil. MS APPI m/e 205 [M-H]-

References: [1]Patent: US2006/241172,2006,A1 .Location in patent: Page/Page column 63.

4
[ 178546-34-4 ]
[ 74-88-4 ]
[ 1009093-60-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 221 (6.0 g, 31 mmol, 1 eq) in DMF (38 mL) was added K2CO3 (3.0 g, 41 mmol, 1.3 eq), stirred at rt for 10 min, resulting in a suspension. Iodomethane (3.0 mL, 41 mmol, 1.3 eq) was added dropwise and allowed to stir at rt overnight. TLC (9:1 Hexane:EtOAc) showed no remaining 221. The mixture was diluted into water and extracted with EtOAc. The organic was separated, washed with brine, dried, filtered and concentrated in vacuo to afford 222 as an oil. The crude material was purified by column chromatography (silica gel, 50% DCM in hexane) to afford 2.4 g of 222 as a white solid.

References: [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 14625 - 14628.
Angew. Chem.,2019,vol. 131,p. 14767 - 14770,4.
[2]Patent: US2008/114167,2008,A1 .Location in patent: Page/Page column 185.

5
[ 50-00-0 ]
[ 496-69-5 ]
[ 178546-34-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine; magnesium chloride; In tetrahydrofuran; at 160℃; for 0.25h;Microwave irradiation;	To a solution of MgCl2 (powder 325 mesh, 5.0 g, 52 mmol, 2 eq), paraformaldehyde (3.0 g, 79 mmol, 3 eq) and Et3N (7.0 mL, 52 mmol, 2 eq) in THF (60 mL) was added 220 (5.0 g, 26 mmol, 1 eq), heated in the microwave at 160 C for 15 min. TLC (3:2 Hexane:DCM) showed complete consumption of 220. THF was evaporated and the reaction mixture was taken up in EtOAc, washed with brine, dried, filtered and concentrated in vacuo to afford 5.2 g of 221 which was used without purification. Yield 93%.

References: [1]Patent: US2008/114167,2008,A1 .Location in patent: Page/Page column 184.

6
[ 178546-34-4 ]
[ 96-34-4 ]
[ 550998-61-3 ]

Yield	Reaction Conditions	Operation in experiment
63%		Methyl chloroacetate (7.6 mL, 86.8 mmol) was added to a mixture of <strong>[178546-34-4]3-bromo-5-fluoro-2-hydroxy-benzaldehyde</strong> (9.5 g, 43.4 mmol), tetra-N-butyl-ammonium iodide (1.6 g, 4.34 mmol) and anhydrous potassium carbonate (24 g, 174 mmol). The reaction mixture was heated at 130 C. for 4 h, cooled to 0 C., diluted with tetrahydrofuran (100 mL) and then potassium hydroxide (17 g, 303 mmol) in water (100 mL). The mixture was stirred at rt for 18 h and then, concentrated under reduced pressure. The residue was acidified with HCl and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2; toluene/EtOAc, 40/1) to give 7.0 g (63%) of the product.1H NMR (400 MHz, methyl alcohol-d4) delta ppm 7.66 (s, 1H), 7.47-7.54 (m, 2H).

References: [1]Patent: US2010/331341,2010,A1 .Location in patent: Page/Page column 32.

7
[ 178546-34-4 ]
methyl 2-acetyl-5-fluorobenzofuran-7-carboxylate [ No CAS ]

References: [1]Patent: US2014/275172,2014,A1 .

8
[ 178546-34-4 ]
methyl 5-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran-7-carboxylate [ No CAS ]

References: [1]Patent: US2014/275172,2014,A1 .

9
[ 178546-34-4 ]
(5-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran-7-yl)methanol [ No CAS ]

References: [1]Patent: US2014/275172,2014,A1 .

10
[ 178546-34-4 ]
1-(5-fluoro-7-(hydroxymethyl)benzofuran-2-yl)ethanone [ No CAS ]

References: [1]Patent: US2014/275172,2014,A1 .

11
[ 178546-34-4 ]
(2-acetyl-5-fluorobenzofuran-7-yl)methyl methanesulfonate [ No CAS ]

References: [1]Patent: US2014/275172,2014,A1 .

12
[ 178546-34-4 ]
tert-butyl 3-(4-((2-acetyl-5-fluorobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanoate [ No CAS ]

References: [1]Patent: US2014/275172,2014,A1 .

13
[ 178546-34-4 ]
3-{4-[(2-acetyl-5-fluoro-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl}propanoic acid [ No CAS ]

References: [1]Patent: US2014/275172,2014,A1 .

14
[ 178546-34-4 ]
[ 78-95-5 ]
1-(7-bromo-5-fluorobenzofuran-2-yl) ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;	b) 1-(7-Bromo-5-fluorobenzofuran-2-yl) ethanone Into a 100-mL round-bottom flask was placed <strong>[178546-34-4]3-bromo-5-fluoro-2-hydroxybenzaldehyde</strong> (2 g, 9.13 mmol), 1-chloropropan-2-one (1.1 g, 11.89 mmol), potassium carbonate (2.25 g, 16.28 mmol), and N,N-dimethylformamide (20 mL) and the resulting solution was stirred for 2 h at 80 C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (2*20 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (aq). The resulting mixture was concentrated under vacuum. The resulting residue was purified on a silica gel column with ethyl acetate/petroleum ether (10/90). The collected fractions were combined and concentrated under vacuum to yield 1-(7-bromo-5-fluoro-1-benzofuran-2-yl)ethan-1-one as yellow oil.

References: [1]Patent: US2014/275172,2014,A1 .Location in patent: Paragraph 0535.

15
[ 503-87-7 ]
[ 178546-34-4 ]
5-(3-bromo-5-fluoro-2-hydroxybenzylidene)-2-thioxoimidazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With sodium acetate; In acetic acid; for 12h;Reflux;	General procedure: A mixture of compound 20, aldehyde (0.5 mmol, 1 equiv 20), compound 21 (1.2 equiv), and NaOAc (3 equiv) in glacial AcOH (4 mL) was stirred at reflux (12 h) until no starting material remained, assessed by TLC (SiO2, hexane/ethyl acetate, 1:1, v/v). The reaction mixture was cooled down to room temperature, followed by the addition of iced water. The resulting precipitate was filtered and washed successively with water and Et2O (10 mL). The product was subjected to column purification (hexane/ethyl acetate, 0/35%).

References: [1]Tetrahedron,2016,vol. 72,p. 3554 - 3558.

16
[ 23364-44-5 ]
[ 178546-34-4 ]
C₂₁H₁₇BrFNO₂ [ No CAS ]

References: [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 7927 - 7932.

17
[ 178546-34-4 ]
C₈H₇BrFNO₂ [ No CAS ]