16618-68-1|3-Bromo-5-methoxyaniline| Ambeed

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Quality Control of [ 16618-68-1 ] Purity: 98% SDS Specification

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Product Details of [ 16618-68-1 ]

CAS No. :	16618-68-1
Formula :	C₇H₈BrNO
M.W :	202.05
SMILES Code :	COC1=CC(N)=CC(Br)=C1
MDL No. :	MFCD11878497
InChI Key :	FHUSNGUPJXGLPL-UHFFFAOYSA-N
Pubchem ID :	14998828

Safety of [ 16618-68-1 ]

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

Computational Chemistry of [ 16618-68-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	45.04
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.25 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.87
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	1.9
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.05
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.	1.91
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	1.78
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.9

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.67
Solubility	0.434 mg/ml ; 0.00215 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.	-2.26
Solubility	1.1 mg/ml ; 0.00546 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	-3.02
Solubility	0.192 mg/ml ; 0.000948 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.	-6.18 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)	1.72

Application In Synthesis of [ 16618-68-1 ]

* 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.

Upstream synthesis route of [ 16618-68-1 ]
Downstream synthetic route of [ 16618-68-1 ]

[ 16618-68-1 ] Synthesis Path-Upstream 1~1

1
[ 16618-68-1 ]
[ 557-21-1 ]
[ 269411-71-4 ]

References: [1] Patent: US6369226, 2002, B1, . Location in patent: Page column 13.

[ 16618-68-1 ] Synthesis Path-Downstream 1~41

1
[ 16618-67-0 ]
[ 16618-68-1 ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With palladium on activated charcoal; hydrogen; In methanol; acetone; at 20℃; for 3h;	The 30.0g dinitrobenzene (0.18mmol) dissolved in 180 ml of concentrated sulfuric acid, heating to 80 C, can keep the temperature in 80-90 C between, the 44.5gNBS (0.25mol) is divided into nine batches to add to the above-mentioned solution, the reaction continued for 30 min, cooling the caster enters 600 ml ice water, separating white precipitation, filtration, washing, drying to obtain the white solid 3,5-dinitro-bromophenylacetic 41.3g, yield 93.7% ; measure 1g sodium (43.4mmol) dissolved in methanol to prepare a solution of sodium methylate, will 8.7g3,5-dinitro-bromobenzene (35.2mmol) by adding the above methanol solution of sodium, 45 C reflux reaction 2h, after cooling to room temperature, using 50mL1N after treatment of the hydrochloric acid solution, dichloromethane is used for extraction, the combined organic was saturated salt water washing 3 times, water-free magnesium sulfate drying, filtering drying solvent, crude column separation (petroleum ether: dichloromethane = 5:1) to obtain white powdery solid 3-methoxy-5-nitro-bromophenylacetic 4.6g, yield: 56.3% ; the 400mgPd/C adding 2.32g3-methoxy-5-nitro-bromobenzene (10mmol) dissolved in 25 ml methanol with 10 ml acetone in the solution, the hydrogen reaction at room temperature under the conditions of 3h, is filtered to remove Pd/C, to evaporate the solvent, column separation (petroleum ether: ethyl acetate = 4:1) to obtain light yellow solid 1.95g, yield: 96.5%.
95%	With water; tin(ll) chloride; In ethanol; for 2h;Heating / reflux;	Example 25 Synthesis of 3-Bromo-5-methoxy-phenylamine (CX) A slurry of 1-bromo-3-methoxy-5-nitrobenzene (9.9 g, 43 mmol) in EtOH (140 ml) was slowly added at RT to SnCl2.2R2O (48 g, 213 mmol). The mixture was refluxed for 2 h, cooled to RT, and poured into ice/water mixture (150 ml). A solution of NaOH (12 M, 250 ml) was added until the pH>12. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in CHCl3 (30 ml) and filtered. The filtrate was concentrated to afford 3-Bromo-5-methoxy-phenylamine CX as an off-white solid (8.2 g, 95% yield).
92%	With ammonium chloride; zinc; In tetrahydrofuran; water; at 20℃; for 0.5h;	b) To a solution of 1-bromo-3-methoxy-5-nitrobenzene (1 g, 4.33 mmol) in THF (10 ml) were added a solution of ammonium chloride (1.83 g, 34.6 mmol, 8 eq.) in water (5 ml) and zinc (1.93 g, 34.6 mmol, 8 eq.). The mixture was stirred at RT for 30 min and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off to afford the product in 92% yield (0.8 g).

54%	With hydrogenchloride; iron; acetic acid; In methanol; water; at 109℃; for 1h;	In a 100 mL round bottom flask, 1-bromo-3-methoxynitrobenzene (4.64 g, 20 mmol) and iron powder (5.6 g) were added.100 mmol) of acetic acid/methanol/water mixed solvent (20 mL) was added to the reaction mixture, and a drop of concentrated hydrochloric acid was added to the reaction mixture. The reaction was carried out at 109 C. for 1 h and then at room temperature for 4 h.20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×2), and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate gradient elution) to give yellow The solid was 3-bromo-5-methoxyaniline 2.15g, yield 54%.
7.98 g	With ammonium chloride; In methanol; water; at 95℃; for 2h;	To a solution of 1-bromo-3-methoxy-5-nitrobenzene (6) (50.0mmol) in MeOH: H2O (1:1, 150mL) was added carbonyl iron (250mmol, 14.0g) and ammonium chloride (21.4g, 400mmol) at RT and mixture was stirred at 95C for 2h. The mixture was cooled to RT, adjusted to pH 8 with aq. sat. Na2CO3 and filtered over celite (particle size 0.02-0.1mm). The filtrate was concentrated in vacuo, aqueous residue diluted with H2O (200mL) and extracted with EtOAc (3×250mL). The combined organic layer was dried over Na2SO4, concentrated and dried in vacuo to give 3-bromo-5-methoxyaniline as a dark solid (7.98g, 79% over two steps). Rf 0.47 (CH2Cl2 100%); 1H NMR (500MHz, CDCl3) delta=6.46 (1H, t, 4J 1.9), 6.44 (1H, t, 4J 1.8) 6.13 (1H, t, 4J 2.1), 3.74 (3H, s, OCH3), 3.70 (2H, br, NH2); 13C NMR (125MHz, CDCl3) delta=161.3 (C5), 148.6 (C3), 123.3 (C1), 110.9 (C2), 107.3 (C6), 99.9 (C4), 55.3 (OCH3); Analytical data is in agreement with literature [16c].

References: [1]Patent: CN103497211,2016,B .Location in patent: Paragraph 0074; 0075.
[2]Patent: US2007/123527,2007,A1 .Location in patent: Page/Page column 79.
[3]Patent: US2015/11548,2015,A1 .Location in patent: Paragraph 0788.
[4]Organic Letters,2016,vol. 18,p. 2774 - 2776.
[5]Journal of Medicinal Chemistry,2014,vol. 57,p. 4889 - 4905.
[6]Patent: CN107973727,2018,A .Location in patent: Paragraph 0152.
[7]Journal of the Chemical Society,1926,p. 2078.
[8]Journal of the Chemical Society. Perkin transactions II,1977,p. 14 - 17.
[9]Tetrahedron,2018,vol. 74,p. 5486 - 5493.

2
[ 16618-68-1 ]
[ 855400-66-7 ]

References: [1]Journal of the Chemical Society,1926,p. 2827.

3
[ 16618-68-1 ]
[ 915412-18-9 ]

References: [1]Journal of the Chemical Society,1926,p. 2078.

4
[ 6191-99-7 ]
[ 16618-68-1 ]
[ 917833-39-7 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 0 - 20℃; for 0.5h;	To 14 mL of a pyridine solution containing 1.4 g of <strong>[16618-68-1]3-bromo-5-methoxyaniline</strong>, 1.0 g of (2E)-3-ethoxyacryloyl chloride was added under cooling with ice, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was fed into ice water, and the precipitate was collected by filtration. Ethyl acetate and water were added thereto, and the resultant solution was adjusted to pH 4.0 with 1 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.7 g of a light brown solid, (2E)-N-(3-bromo-5-methoxyphenyl)-3-ethoxyacrylamide. 1H-NMR (CDCl3) delta: 1.26 (3H, t, J=7.1 Hz), 3.79 (3H, s), 3.96 (2H, q, J=7.1 Hz), 5.28 (1H, d, J=12.1 Hz), 6.79 (1H, t, J=1.9 Hz), 6.87 (1H, s), 7.20 (1H, t, J=1.9 Hz), 7.24 (1H, t, J=1.9 Hz), 7.63 (1H, d, J=12.1 Hz)

References: [1]Patent: EP1900732,2008,A1 .Location in patent: Page/Page column 53.

5
[ 16618-68-1 ]
[ 106120-04-1 ]

References: [1]Journal of the Chemical Society,1926,p. 2827.

6
[ 16618-68-1 ]
[ 557-21-1 ]
[ 269411-71-4 ]

References: [1]Patent: US6369226,2002,B1 .Location in patent: Page column 13.

7
[ 16618-68-1 ]
[ 2032-35-1 ]
[ 938061-52-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; for 72h;Heating / reflux;	Synthesis of (3-Bromo-5-methoxy-phenyl)-(2,2-diethoxy-ethyl)-amine (CXI) A solution of 3-Bromo-5-methoxy-phenylamine CX (4.0 g, 20 mmol), bromoacetaldehyde diethyl acetal (3.1 ml, 20 mmol) and NaHCO3 (1.8 g, 21 mmol) in DMF (25 ml) was stirred at reflux for 72 hours. The mixture was cooled to room temperature and the solvent was partially evaporated. The residue was dissolved in Et2O (100 ml), washed with H2O (50 ml) and brine (25 ml), dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording the compound CXI as a yellow oil (4.8 g, 75% yield).

References: [1]Patent: US2007/123527,2007,A1 .Location in patent: Page/Page column 79.

8
[ 16618-68-1 ]
[ 141-75-3 ]
[ 1056894-18-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 5 - 20℃; for 1h;	a)..Prep aration o f .intermediate 34; A solution of butanoyl chloride (0.0292 mol) in DCM (10ml) was added dropwise to a solution of 3-bromo-5-methyloxybenzenamine (0.0292 mol) and Et3N (0.035 mol) in DCM (50ml) at 5C under N2 flow. The mixture was stirred at room temperature for 1 hour. K2CO3 10% was added and the organic layer was decanted, dried (MgSO4), filtered off and evaporated till dryness, yielding 8 g (100%) of intermediate 34.

References: [1]Patent: WO2009/53373,2009,A1 .Location in patent: Page/Page column 60.

9
[ 16618-68-1 ]
[ 1332626-21-7 ]