357405-75-5|4-Bromo-2,5-difluorobenzaldehyde| Ambeed

Structure of 357405-75-5

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Quality Control of [ 357405-75-5 ] Purity: 98% SDS Specification

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Product Details of [ 357405-75-5 ]

CAS No. :	357405-75-5
Formula :	C₇H₃BrF₂O
M.W :	221.00
SMILES Code :	FC1=CC(C=O)=C(F)C=C1Br
MDL No. :	MFCD11847047
Boiling Point :	No data available
InChI Key :	PDRHYPUKWIHZMP-UHFFFAOYSA-N
Pubchem ID :	22489081

Safety of [ 357405-75-5 ]

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

Computational Chemistry of [ 357405-75-5 ] 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	0.0
Molar Refractivity	39.45
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	17.07 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.8
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	2.28
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.38
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.	3.05
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	3.5
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.8

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.98
Solubility	0.229 mg/ml ; 0.00104 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.	-2.28
Solubility	1.17 mg/ml ; 0.0053 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	-3.76
Solubility	0.0381 mg/ml ; 0.000172 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.	-6.03 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	2.0 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)	1.36

Application In Synthesis of [ 357405-75-5 ]

* 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 [ 357405-75-5 ]

[ 357405-75-5 ] Synthesis Path-Downstream 1~35

1
[ 357405-75-5 ]
[ 2950-43-8 ]
[ 133541-45-4 ]

Yield	Reaction Conditions	Operation in experiment
	In water;	b 4-Bromo-2,5-difluorobenzonitrile <strong>[357405-75-5]4-Bromo-2,5-difluorobenzaldehyde</strong> (1.82 g, 8.3 mmol) and hydroxylamin-O-sulphonic acid (1.1 eq., 1.03 g) in water (40 ml) were heated to 100° C. for 6 h, cooled and extracted with ethyl acetate. The organic layer was dried (sodium sulphate) and evaporated to give the title compound as a pale yellow solid (1.2 g). 1H NMR 300 MHz (CDCl3) 7.51 (1H, t), 7.39 (1H, t).

References: [1]Patent: US2003/158185,2003,A1 .

2
[ 109-72-8 ]
[ 327-51-5 ]
[ 357405-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether;	a 4-Bromo-2,5-difluorobenzaldehyde n-Butyllithium (1.95M in hexanes, 10.2 ml)) was added dropwise to a stirred solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in diethyl ether (60 ml) at -70° C. After 1 h, the solution was warmed to 0° C. over 1 h, diluted with water, the layers separated and the ether layer dried over sodium sulphate and evaporated. Purification by column chromatography (Biotage), eluding with 5percent ethyl acetate/hexane, gave a yellow oil (1.82 g). 1H NMR 300 MHz (CDCl3) 10.28 (1H, s), 7.61 (1H, dd), 7.48 (1H, dd).

References: [1]Patent: US2003/158185,2003,A1 .

3
[ 327-51-5 ]
[ 357405-75-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With ammonium chloride; In tetrahydrofuran; N,N-dimethyl-formamide;	Method 6 4-Bromo-2,5-difluorobenzaldehyde To 1,4-dibromo-2,5-difluorobenzene (10.28 g, 37.81 mmol) in tetrahydrofuran (80 mL) at -40° C. was isopropylmagnesium chloride lithium chloride complex (29.1 mL, 37.81 mmol) added dropwise. After 1 h at -40° C. was N,N-dimethylformamide (58 mL, 756 mmol) added and the mixture was stirred for 30 minutes at -40° C. NH4Cl (2M, aq, 100 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated to give 4-bromo-2,5-difluorobenzaldehyde (6.20 g, 74percent) as a solid. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 10.28 (d, 1H) 7.61 (dd, 1H) 7.48 (dd, 1 H).

References: [1]Patent: US2010/267723,2010,A1 .

4
[ 327-51-5 ]
[ 68-12-2 ]
[ 357405-75-5 ]

Yield	Reaction Conditions	Operation in experiment
86%		Example 31 Preparation of 4-bromo-2,5-difluorobenzaldehyde [0289] 2,5-dibromo-1,4-difluorobenzene (10.0 g, 36.77 mmol) in diethyl ether (150 mL) at -78 C. was added n-butyl lithium (2.5 M in Hexanes, 14.86 mL, 37.15 mmol) dropwise under nitrogen. The reaction mixture was stirred at -78 C. for 30 min. Dry DMF (3.13 mL, 40.46 mmol) in diethyl ether (10 mL) was added dropwise and reaction was slowly warmed to room temperature over 2 h. The reaction was quenched with aqueous saturated ammonium chloride solution (25 mL) and extracted with diethyl ether. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure (Note: Product is highly volatile). The crude product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in hexanes) to provide the title compound as a pale yellow solid (7.0 g, 86%): 1H NMR (400 MHz, CDCl3): delta 7.50 (dd, J=5.08, 8.92 Hz, 1H), 7.62 (dd, J=5.80, 7.68 Hz, 1H), 10.30 (d, J=2.76 Hz, 1H).
66.7%		To a stirred solution of XXXII-1 (12 g, 44.1 mmol) in THF (150 mL) was added dropwise of XXXII-1A (44.1 mmol, 34 mL, 1.3 M) at -40 C. After stirred 1 h at -40 C., DMF (64 g, 882 mmol) was added and the mixture was stirred overnight. NH4Cl (aq., 2M) was added and the mixture was extracted with EtOAc. The organic phase was dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (PE/EA=10/1) to afford XXXII-2 (6.5 g, yield: 66.7%).
55.8%		To a solution of l,4-dibromo-2,5-difluorobenzene (15 g, 55 mmol) in toluene (600 mL) cooled to -78 C was added butyllithium (22 mL, 55 mmol) and the reaction was kept at -78 C for 30 minutes. N,N-dimethylformamide (4.4 g, 61 mmol) was added and the reaction was stirred for 2 hours while warming to ambient temperature. To the reaction was added water (200 mL) and EtOAc (400 mL) and the organic layers were separated. The organic layer was washed with brine (200 mL), dried over MgS04, filtered and concentrated in vacuo. The crude material was chromatographed eluting with 5% EtOAc/Hexane to yield 4-bromo-2,5-difluorobenzaldehyde (6.7 g, 55.8%).

37%		n-Butyl lithium (3.6 ml,7.7 mmol) was added drop wise to a solution of 1,4- dibromo-2,5-difluoro-benzene (2g, 7.35mmol) in dry ether at -78C under nitrogen atmosphere and the resulting mixture was stirred at -78C for 30 minutes. This was followed by the addition of DMF (0.85ml, 11.03mmol) in dry THF. The resultant was stirred at room temperature for 1 hour. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography on silica gel (2% ethyl acetate in hexane) to afford 600mg of the product (37% yield).1H NM (CDC13, 300 MHZ): delta 10.27-10.26 (d, 1H), 7.61-7.57 (t, 1H), 7.49- 7.44 (q, 1H)
		To a Et2O solution (200 mL) containing 1,4-dibromo-2,5-difluorobenzene (19.72 g, 72.5 mmol) cooled to -78 degrees C. was added 30.5 mL of a 2.5 M hexanes solution of n-BuLi (76.2 mmol). The resulting green solution was stirred for 20 min at -78 degrees C. when DMF (7.95 g, 10.8 mmol) was added. The reaction was stirred for 30 min and then quenched with H2O. The organics were taken up in EtOAc and washed with sat. NaHSO4 followed by drying over MgSO4. The solvent was removed in vacuo and the residual oil purified on the Biotage (2-5% EtOAc/hexanes) yielding 11.4 g (51.7 mmol) of 4-bromo-2,5-difluorobenzaldehyde. 1H NMR (400 MHz, CDCl3) delta 10.2 (s, 1H), 7.57 (m, 1H), 7.45 (m, 1H) ppm.

References: [1]Patent: US2014/274696,2014,A1 .Location in patent: Paragraph 0289; 0290.
[2]Patent: US2014/200215,2014,A1 .Location in patent: Paragraph 1205; 1206.
[3]Patent: WO2013/74641,2013,A1 .Location in patent: Paragraph 00350.
[4]Patent: WO2012/149413,2012,A1 .Location in patent: Page/Page column 63.
[5]Patent: US2010/222345,2010,A1 .Location in patent: Page/Page column 97.
[6]Advanced Materials,2019,vol. 31.

5
[ 110-91-8 ]
[ 357405-75-5 ]
[ 1252575-79-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; In dichloromethane; water; ethyl acetate;	Method 10 4-(4-bromo-2,5-difluorobenzyl)morpholine <strong>[357405-75-5]4-Bromo-2,5-difluorobenzaldehyde</strong> (15.8 g, 60.8 mmol) was dissolved in dichloromethane (150 mL) and stirred under nitrogen. Morpholine (5.83 mL, 66.9 mmol) was added followed by sodium triacetoxyborohydride (16.74 g, 79.0 mmol) portionwise (4*). The mixture was stirred at ambient temperature over night. The reaction was quenched with saturated NaHCO3 (aq, 80 mL). The phases were separated. To the organic phase was added hydrochloric acid (aq, 2M, 80 mL). The mixture was stirred for 20 min. A solid was isolated by filtration. To the solid was 2M NaOH (60 mL), H2O (60 mL) and EtOAc (100 mL) added. The mixture was stirred for 15 min. The phases were separated and the organic phase was concentrated to give the title compound as a solid (17.8 g, 60.9 mmol, 100percent. 1H NMR (500 MHz, DMSO-d6) delta ppm 7.69 (dd, 5.83 Hz, 1H) 7.42 (dd, 1H) 3.53-3.60 (m, 4H) 3.48 (d, 2H) 2.30-2.47 (m, 4H). MS (ES+) m/z 292 (M+H)+.

References: [1]Patent: US2010/267723,2010,A1 .

6
[ 357405-75-5 ]
[ 1022094-03-6 ]
[ 1252575-76-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; triethylamine; In 1,1-dichloroethane;	Method 5 (S)-4-(4-Bromo-2,5-difluorobenzyl)-3-methylmorpholine <strong>[357405-75-5]4-Bromo-2,5-difluorobenzaldehyde</strong> (331 mg, 1.5 mmol), (S)-3-methylmorpholine hydrochloride (206 mg, 1.50 mmol) and sodium triacetoxyborohydride (461 mg, 2.18 mmol) were mixed in dichloroethane (5 mL). Triethylamine (0.230 mL, 1.65 mmol) was added and the resulting mixture was stirred at RT under argon atmosphere for 24 h. NaHCO3 (25 mL) was added and the mixture was extracted with dichloromethane (3*25 mL).

References: [1]Patent: US2010/267723,2010,A1 .

7
[ 357405-75-5 ]
[ 141-43-5 ]
[ 1373233-55-6 ]

Yield	Reaction Conditions	Operation in experiment
90%		difluorobenzylamino)ethanol was prepared as described below:<strong>[357405-75-5]4-Bromo-2,5-difluorobenzaldehyde</strong> (1.0 g, 4.52 mmol) was dissolved in degassed DCE (25 mL) and stirred under nitrogen. 2-Aminoethanol (0.238 mL, 4.52 mmol) was added followed by sodium triacetoxyborohydride (2.398 g, 11.31 mmol) portionwise. The mixture was stirred at room temperature for 3 hours. Sodium carbonate (aq) was added. The phases were separated and the organic phase was extracted with HC1 (2M, aq). The aquous phase was neutralized with KOH (s) and was extracted with dichloromethane (x3). The combined organic phases were dried and evaporated to give the title compound (1.2 g, 90percent) that was used without further purification.MS (APCI+) m/z 266 [M+H]+.

References: [1]Patent: WO2012/50517,2012,A1 .Location in patent: Page/Page column 23.

8
[ 357405-75-5 ]
[ 57260-73-8 ]
[ 501-53-1 ]
[ 1437800-76-4 ]