169045-04-9|2-Amino-5-bromo-4-methoxybenzoic acid| Ambeed

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Quality Control of [ 169045-04-9 ] Purity: 95% SDS Specification

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Product Details of [ 169045-04-9 ]

CAS No. :	169045-04-9
Formula :	C₈H₈BrNO₃
M.W :	246.06
SMILES Code :	O=C(O)C1=CC(Br)=C(OC)C=C1N
MDL No. :	MFCD21868786
InChI Key :	YTAASTFSTXYEIX-UHFFFAOYSA-N
Pubchem ID :	19701926

Safety of [ 169045-04-9 ]

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

Computational Chemistry of [ 169045-04-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	52.0
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	72.55 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.52
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	1.98
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.75
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.	0.37
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	1.19
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.36

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.82
Solubility	0.37 mg/ml ; 0.0015 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.	-3.13
Solubility	0.183 mg/ml ; 0.000742 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	-2.4
Solubility	0.984 mg/ml ; 0.004 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	No
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.	-6.4 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.	0.56

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)	1.55

Application In Synthesis of [ 169045-04-9 ]

* 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 [ 169045-04-9 ]

[ 169045-04-9 ] Synthesis Path-Downstream 1~35

1
[ 169045-04-9 ]
[ 861298-96-6 ]

References: [1]Journal of the Chemical Society,1925,vol. 127,p. 995.

2
[ 861298-97-7 ]
[ 169045-04-9 ]

References: [1]Journal of the Chemical Society,1925,vol. 127,p. 995.

3
[ 50868-75-2 ]
[ 169045-04-9 ]

References: [1]Journal of the Chemical Society,1925,vol. 127,p. 995.

4
[ 871878-59-0 ]
[ 169045-04-9 ]

References: [1]Journal of the Chemical Society,1925,vol. 127,p. 995.

5
[ 169045-04-9 ]
[ 3473-63-0 ]
[ 950577-05-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	In ethanol; for 24.0h;Heating / reflux;	6-bromo-7-methoxyquinazoline-4(3H)-one <strong>[169045-04-9]2-amino-5-bromo-4-methoxybenzoic acid</strong> (type T) (5.63 g, 23 mmol) was dissolved in EtOH (100 mL), formamidine acetate (4.76 g, 46 mmol) added and refluxed for 1 d. Water (200 mL) was then added, the precipitated product filtered out and washed with 70% ethanol. (Yield: 4.14 g, 71%)

References: [1]Patent: US2009/69320,2009,A1 .Location in patent: Page/Page column 68.

6
[ 4294-95-5 ]
[ 169045-04-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.0h;	To a solution of 2-amino-4-methoxybenzoic acid (4.00 g, 23.93 mmol) in DMF (120 mL) at 0 C was added NBS (4.68 g, 26.3 mmol). The cooling bath was removedand the reaction mixture was warmed up to room temperature and was stirred at room temperature for 1 h. The mixture was cooled to 0 C and was treated with saturated sodium sulfite solution (25 mL) and was stirred for 5 mm. The pH of the mixture was adjusted to pH = 3 using conc. HC1 (ca. 10-15 mL was added). The reaction mixture was transferred to a separatory funnel containing water (100 mL). Theaqueous layer was extracted with ether (1 x 250 mL then 4 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated to afford 2-amino-5-bromo-4- methoxybenzoic acid (5.90 g, 100% yield) as a solid: ?H NMR (400 MHz, DMSOd6) oe 7.78 (s, 1H), 6.43 (s, 1H), 3.81 (s, 3H), 2.90 (s, 1H), 2.74 (s, 1H); MS (ESI) m/e228.0 [(M+H-H2O), calcd for C8H7BrNO2 228.0].
77%	With bromine; acetic acid; at 20 - 40℃; for 18.0h;	2-amino-5-bromo-4-methoxybenzoic acid 2-amino-4-methoxybenzoic acid (5 g, 30 mmol) was suspended in acetic acid (100 mL) and bromine (0.57 mL, 11.25 mmol) added at RT. The mixture was stirred approx. 15 h at RT, then additional bromine (0.2 mL, 3.75 mmol) was added and the reaction mixture held at 40 C. for 3 hours. The reaction course was tracked by thin-film chromatography, the product filtered out and washed with a little water. (Yield: 5.63 g, 77%)
	With bromine; In acetic acid; at 0 - 20℃; for 8.0h;	Step 1: 2-Amino-5-bromo-4-methoxybenzoic acidTo a stirred suspension of 2-amino-4-methoxybenzoic acid (5 g, 0.029 mol) in acetic acid (100 mL) was added bromine (1.23 mL, 0.023 mol) dropwise at 0C. The reaction mixture was stirred at room temperature for 8 h. The separated solid was filtered, washed with water (30 mL) and dried under vacuum to afford the product as white solid (6.3 g, 86 %). As per the LC-MS data this solid contains 14% of starting material, 22% of dibromo byproduct and 61% of desired compound.1H NMR (400 MHz, DMSO-de) : delta 7.76 (s, 1H), 6.42 (s, 1H), 3.72 (s, 3H); ESI-MS: Calculated mass: 244.97; Observed mass LC-MS: 246.0 [M + H]+RT: 2.07 min.

1.3 g	With N-Bromosuccinimide; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 4.0h;	To a mixture of 4-methoxyanthranilic acid (0.67 g, 4.0 mmol) in DCM (10 mL) and DMF (3 mL) was added NBS (0.71 g, 4.0 mmol) at 0 C. The mixture was stirred at room temperature for 4 h, then concentrated and subjected to silica gel chromatography (5-100% EtOAc/Heptane) to provide 2-amino-5-bromo-4-methoxybenzoic acid as a beige solid (1 .30 g, containing 1 equivalent succinamide). MS (M-1 ) = 244.3/246.3. 1H NMR (DMSO-d6) delta 7.76 (s, 1 H), 6.42 (s, 1 H), 3.79 (s, 3H). This material was used without further purification.
	With bromine; acetic acid; In acetonitrile; at 0 - 20℃; for 1.0h;Inert atmosphere;	2-Amino-4-methoxybenzoic acid (5.00 g, 29.91 mmol) was dissolved in acetic acid (10 mL) and acetonitrile (100 mL), slowly added dropwise with liquid bromine (4.78 g, 29.91 mmol) at 0 C and under nitrogen protection,, and stirred at 20 C for 1 hour. TLC showed that the reaction was complete. After the reaction solution was concentrated, water (100 ml) and petroleum ether (100 ml) were successively used for making a slurry, which was vaccum dried to obtain compound 1A. 1H NMR (400MHz, DMSO-d6) delta= 7.76 (s, 1H), 6.41 (s, 1H), 3.79 (s, 3H).

References: [1]Patent: WO2016/53794,2016,A1 .Location in patent: Page/Page column 111.
[2]Patent: US2009/69320,2009,A1 .Location in patent: Page/Page column 68.
[3]Patent: WO2014/169167,2014,A1 .Location in patent: Page/Page column 87.
[4]Patent: WO2015/17589,2015,A1 .Location in patent: Page/Page column 98.
[5]Patent: EP3567030,2019,A1 .Location in patent: Paragraph 0136-0137.

7
[ 290-87-9 ]
[ 169045-04-9 ]
[ 950577-05-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	With piperidine; In methanol; for 1.0h;Heating / reflux;	6-Bromo-7-methoxy-3H-quinazolin-4-one 2-Amino-5-bromo-4-methoxybenzoic acid (1.56 g, 6.34 mmol) is dissolved in methanol (15 ml), treated with piperidine (0.063 ml, 0.63 mmol) and 1,3,5-triazine (772 mg, 9.5 mmol) and refluxed for one hour. After cooling to room temperature, the resulting crystals are filtered off with suction and washed with methanol. The desired product is obtained in 63% yield (1.01 g). 1H-NMR (300 MHz, DMSO-d6): delta 3.95 (s, 3H), 7.20 (s, 1H), 8.08 (s, 1H), 8.16 (s, 1H), 12.2 (br, 1H).

References: [1]Patent: US2009/186911,2009,A1 .Location in patent: Page/Page column 39-40.

8
[ 169045-04-9 ]
6-bromo-7-methoxyquinazoline-2,4(1H,3H)-dione [ No CAS ]

References: [1]Patent: WO2014/169167,2014,A1 .

9
[ 169045-04-9 ]
6-bromo-2,4-dichloro-7-methoxyquinazoline [ No CAS ]

References: [1]Patent: WO2014/169167,2014,A1 .

10
[ 169045-04-9 ]
4-(6-bromo-2-chloro-7-methoxy-4,4a-dihydroquinazolin-4-yl)morpholine [ No CAS ]

References: [1]Patent: WO2014/169167,2014,A1 .

11
[ 169045-04-9 ]
N-(3-(2-chloro-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide [ No CAS ]

References: [1]Patent: WO2014/169167,2014,A1 .

12
[ 169045-04-9 ]
N-(3-(2-(2-aminopyrimidin-5-yl)-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide [ No CAS ]

References: [1]Patent: WO2014/169167,2014,A1 .

13
[ 169045-04-9 ]
[ 74-88-4 ]
[ 169044-96-6 ]

Yield	Reaction Conditions	Operation in experiment
5.5 g	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.0h;	Step 2: Methyl 2-amino-5-bromo-4-methoxybenzoateTo a stirred suspension of <strong>[169045-04-9]2-amino-5-bromo-4-methoxybenzoic acid</strong> (6.3 g, 0.025 mol) and potassium carbonate (7.06 g, 0.051 mol) in N,ll-dimethyl formamide (63 mL) was added methyl iodide (5.45 g, 0.038 mol) dropwise at 0C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into ice cold water (500 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (100 mL) followed by brine solution, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using column chromatography (100-200 mesh silica gel, 20% EtOAc in hexane) to afford the title compound as white solid (5.5 g, 83% yield). *H NMR (400 MHz, DMSO-d6) : delta 7.78 (s, 1H), 6.85 (brs, 2H), 6.44 (s, 1H), 3.80 (s, 3H), 3.75 (s, 3H). ESI-MS: Calculated mass: 258.98; Observed mass: 258.3 [M-H]

References: [1]Patent: WO2014/169167,2014,A1 .Location in patent: Page/Page column 87; 88.

14
[ 169045-04-9 ]
7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4(1H)-one [ No CAS ]

References: [1]Patent: WO2015/17589,2015,A1 .

15
[ 169045-04-9 ]
7-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinazolin-4(1H)-one [ No CAS ]

References: [1]Patent: WO2015/17589,2015,A1 .

16
[ 169045-04-9 ]
[ 3473-63-0 ]
6-bromo-7-methoxyquinazolin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.858 g	In ethanol; for 24.0h;Reflux;	A mixture of <strong>[169045-04-9]2-amino-5-bromo-4-methoxybenzoic acid</strong> (1 .25 g, 3.6 mmol) and formimidamide acetate (0.75 g, 7.2 mmol) in EtOH (15 mL) was refluxed for 24 h. The mixture was cooled to room temperature and the solid was filtered, washed with water, and dried to provide 6- bromo-7-methoxyquinazolin-4(1 H)-one as a white solid (0.858 g). MS (M+1 ) = 255.0/257.0. 1H NMR (DMSO-d6) delta 12.30 (br. s, 1 H), 8.21 (s, 1 H), 8.12 (s, 1 H), 7.25 (s, 1 H), 4.00 (s, 3H).

References: [1]Patent: WO2015/17589,2015,A1 .Location in patent: Page/Page column 98.

17
[ 169045-04-9 ]
benzyl 1-(7-methoxy-4-oxo-6-(pyridin-4-yl)-3,4-dihydroquinazolin-2-yl)-3-methylbutylcarbamate [ No CAS ]