627531-47-9|4-Bromo-3-chloro-2-methylaniline| Ambeed

CAS No. :	627531-47-9
Formula :	C₇H₇BrClN
M.W :	220.49
SMILES Code :	CC1=C(N)C=CC(Br)=C1Cl
MDL No. :	MFCD07369999
InChI Key :	IAWSZYHMEPZGKK-UHFFFAOYSA-N
Pubchem ID :	7171911

Safety of [ 627531-47-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338

Computational Chemistry of [ 627531-47-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	0
Num. H-bond acceptors	0.0
Num. H-bond donors	1.0
Molar Refractivity	48.52
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.03
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	2.83
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.0
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.	3.15
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	2.88
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.78

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.43
Solubility	0.0812 mg/ml ; 0.000368 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.	-3.03
Solubility	0.204 mg/ml ; 0.000924 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	-3.9
Solubility	0.0277 mg/ml ; 0.000126 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	Yes
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.	-5.64 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)	1.46

Application In Synthesis of [ 627531-47-9 ]

* 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 [ 627531-47-9 ]

[ 627531-47-9 ] Synthesis Path-Downstream 1~54

1
[ 71862-02-7 ]
[ 627531-47-9 ]

References: [1],.
[2],.

Yield	Reaction Conditions	Operation in experiment
83%		22B. 4-Bromo-3-chloro-2-methylaniline The title compound was prepared (0.70 g, 83% yield) from 22A in a manner similar to that described in Experiment 2D.

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Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; In ethanol; water; at 80℃; for 5h;	100ml flask-N (4-bromo-3 - chloro-2-methylphenyl) Oh theta mid 10g (38.09mmol) and the mixture was stirred into a 38ml ethanol. To the reaction mixture into a 38ml HCl 12N (27eq) it was refluxed at 80 for 5 hours. After the completion of the reaction was concentrated under reduced pressure to give the title compound 8.5g (95%).
	With hydrogenchloride; In ethanol;Reflux;	Step C: 4-bromo-3 -chloro-2-methylaniline To a solution of N-(4-bromo-3-chloro-2-methylphenyl)acetamide (18.50 g, 70.5 mmol) in EtOH(70 mL) was added cone. HC1 (70 mL) at room temperature, and the soluation was heated atreflux overnight. The mixture was adjusted to pH7 with solid Na2CO3, and then extracted byEtOAc, dried and concentrated to afford the title compound. LC/MS [M+1] =220; 222. ?HNIVIR (400 IVIFIz, CDC13) 7.24-7.22 (d, J 8.4 Hz, 1H), 6.48-6.46 (d, J 8.4 Hz, 1H), 2.26 (s,3H).
		A solution of N-(4-bromo-3-chloro-2-methyl-phenyl)-acetamide (3.37 g, 12.80 mmol) in H2SO4: H2O (1:1) was refluxed for 3 hours. The reaction mixture was cooled to room temperature and neutralized with NaOH and extracted with Et2O (3×150 mL). The combined organic phases were washed with H2O (3×100 mL) and brine (1×100 mL), then dried over MgSO4 and concentrated. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded the title aniline. Spectroscopic data: 1H NMR (300 MHz, CDCl3) delta 2.31 (s, 3H), 3.93 (br s, 2H), 6.47 (d, J=8.79 Hz, 1H), 7.24 (d, J=7.91 Hz, 1H).

References: [1]Patent: KR2015/123007,2015,A .Location in patent: Paragraph 0258-0262.
[2]Patent: WO2016/8064,2016,A1 .Location in patent: Page/Page column 56; 57.
[3]Patent: US2008/194650,2008,A1 .Location in patent: Page/Page column 24-25.

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[ 97329-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite; In ethanol; water; at 70℃; for 2h;	Concentrated HCl was added to a solution of <strong>[627531-47-9]4-bromo-3-chloro-2-methyl-phenylamine</strong> (4.98 g, 22.60 mmol) in EtOH. NaNO2 (3.00 g, 43.50 mmol) was added and the resulting mixture was heated to 70 C. for 2 hours. Ethanol was distilled off and the residue was purified by column chromatography using hexanes as the eluant to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) delta 2.43 (s, 3H), 7.01 (t, J=7.91 Hz, 1H), 7.18 (d, J=7.62 Hz, 1H), 7.47 (d, J=7.91 Hz, 1H).

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 8363 - 8366.
[2]Patent: US2008/194650,2008,A1 .Location in patent: Page/Page column 24-25.

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[ 1334181-18-8 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 8363 - 8366.

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[ 19482-23-6 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 8363 - 8366.

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Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In acetonitrile; at 10 - 20℃; for 0.5h;	Example 21Preparation of 5-(But-1-yn-1-yl)-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate 37)Step 1: 4-Bromo-3-chloro-2-methylaniline To a solution of 3-chloro-2-methylaniline (30 g, 0.212 mol) in CH3CN (300 mL) was added NBS (45.2 g, 0.254 mol) in portions at 10 C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10 C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether to afford the title compound (30 g), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): delta 7.24 (d, 1H), 6.48 (d, 1H), 3.70 (br, 2H), 2.28 (s, 3H).

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 8363 - 8366.
[2]Patent: US2012/71535,2012,A1 .Location in patent: Page/Page column 56.
[3]Patent: WO2016/8064,2016,A1 .

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[ 1082041-90-4 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; sodium nitrite; In water; at 10 - 20℃; for 0.5h;	Step 2: 5-Bromo-4-chloro-1H-indazole To a solution of <strong>[627531-47-9]4-bromo-3-chloro-2-methylaniline</strong> (11 g, 49.9 mmol) in CH3CO2H (450 mL) was added NaNO2 (5.4 g, 78.3 mmol) in H2O (15 mL) at 10 C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d, 1H).
130 g	With acetic acid; sodium nitrite; at 20℃; for 1h;Cooling with ice;	A solution of sodium nitrite (58.6 g, 0.85 mol) in water (98 ml) was added to an ice bath cooled solution of <strong>[627531-47-9]4-bromo-3-chloro-2-methylaniline</strong> (150 g, 0.68 mol) in acetic acid (3 L)with mechanical stirring andthe mixture was aged for 1H at ambient temperature. Most of the solvent was evaporated and the residue suspended in water (500 mL) and filtered, washing with water (250 ml x 4), petrol (250 ml x 4) and drylng in vacuo at 40C, to give 5-bromo-4-chloro-1H-indazole (130 g), 1H NMR (400 MHz, DMSOde): 13.61 (1H, 5), 8.16 (1H, 5), 7.62 (1H, d), 7.53 (1H, dd).

References: [1]Patent: US2012/71535,2012,A1 .Location in patent: Page/Page column 56-57.
[2]Patent: WO2019/167000,2019,A1 .Location in patent: Page/Page column 161.

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References: [1]Patent: US2012/71535,2012,A1 .

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References: [1]Patent: US2012/71535,2012,A1 .

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 564 - 574.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 564 - 574.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 564 - 574.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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[ 125328-77-0 ]

References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 564 - 574.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 564 - 574.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 564 - 574.

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References: [1]Organic Letters,2013,vol. 15,p. 3766 - 3769.
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 564 - 574.

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