331646-99-2|8-Bromoquinazoline-2,4-diol| Ambeed

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Quality Control of [ 331646-99-2 ] Purity: 95% SDS Specification

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Product Details of [ 331646-99-2 ]

CAS No. :	331646-99-2
Formula :	C₈H₅BrN₂O₂
M.W :	241.04
SMILES Code :	OC1=NC(O)=C2C=CC=C(Br)C2=N1
MDL No. :	MFCD11499006
InChI Key :	XAKSYDAOQDFHDD-UHFFFAOYSA-N
Pubchem ID :	22457660

Safety of [ 331646-99-2 ]

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

Computational Chemistry of [ 331646-99-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	10
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	51.28
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	66.24 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.79
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	2.19
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.8
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.	1.22
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	1.62
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.73

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.28
Solubility	0.126 mg/ml ; 0.000521 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.	-3.21
Solubility	0.147 mg/ml ; 0.00061 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	-3.04
Solubility	0.221 mg/ml ; 0.000918 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.	-6.22 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	0.0 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)	1.76

Application In Synthesis of [ 331646-99-2 ]

* 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 [ 331646-99-2 ]

[ 331646-99-2 ] Synthesis Path-Downstream 1~35

1
[ 331646-99-2 ]
[ 331647-05-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With trichlorophosphate; In N,N-dimethyl-formamide; at 130.0℃; for 12.0h;	To a mixture of 8-bromoquinazoline-2,4(lH,3H)-dione (12.1 g, 50 mmol, 1 eq.) in POCl3(130 mL) was added DMF (0.5 mL). The mixture was stirred at 130 C for 12 h, then cooled to r.t. and concentrated. The resulting residue was dissolved in EA (100 mL) and poured into ice-water with vigorous stirring. The organic phase was separated and washed with brine, dried over anhydrous Na2S04and concentrated. The resulting residue was purified via column chromatography (PE/EA==10: 1, v/v) to afford 8-bromo-2,4- dichloroquinazoline as a yellow solid (9.1 g, 60% yield).
60%	With trichlorophosphate; In N,N-dimethyl-formamide; at 130.0℃; for 12.0h;	[0287] To a mixture of <strong>[331646-99-2]8-bromoquinazoline-2,4(1H,3H)-dione</strong> (12.1 g, 50 mmol, 1 eq.) in POC13 (130 mL) was added DMF (0.5 mL). The mixture was stirred at 130 C for 12 h, then cooled to r.t. and concentrated. The resulting residue was dissolved in EA (100 mL) and poured into ice-water with vigorous stirring. The organic phase was separated and washed with brine, dried over anhydrous Na2 SO4 and concentrated. The resulting residue was purified via column chromatography (PE/EA==10:1, v/v) to afford 8-bromo-2,4- dichloroquinazoline as a yellow solid (9.1 g, 60% yield).
0.377 g	With trichlorophosphate; at 100.0℃;	Step B: Phosphorus(V) oxy chloride (4.8 mL, 51.86 mmol, 25.0 eq.) was slowly added to a flask containing 8-bromoquinazoline-2,4(lH,3H)-dione (0.500 g, 2.07 mmol, 1.0 eq.). The mixture was heated to 100 C and the progress of the reaction was monitored by TLC analysis (hexanes/EtOAc 2: 1 v/v). Upon complete consumption of the starting material, the reaction mixture was cooled to room temperature and transferred portionwise to an Erlenmeyer flask containing crushed ice with the aid of CH2CI2. The resulting mixture was stirred for 20 min and then extracted with CH2CI2. The organic phases were combined, washed with saturated aqueous NaHCCb (3x40 mL), brine, dried over Na2SC>4, and concentrated in vacuo. The crude solid was purified by silica gel chromatography to provide 8- bromo-2,4-dichloroquinazoline (0.377 g, 65% yield). XH NMR (400 MHz, CDC13) delta 8.29 (d, J= 7.6 Hz, 1H), 8.26 (d, J= 8.4 Hz, 1H), 7.60 (t, J= 8.1 Hz, 1H). MS (ESI) m/z = 275.00 (M+H)+. LCMS Ret time (UV 214/254): 1.511 min.

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 1523 - 1540.
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 941 - 946.
[4]Patent: WO2015/27222,2015,A2 .Location in patent: Paragraph 0214.
[5]Patent: WO2016/133935,2016,A1 .Location in patent: Paragraph 0287.
[6]Patent: WO2018/212774,2018,A1 .Location in patent: Page/Page column 70.

2
[ 331646-99-2 ]
[ 1262431-78-6 ]

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.

3
[ 331646-99-2 ]
[ 1262431-79-7 ]

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.

4
[ 331646-99-2 ]
[ 1262431-80-0 ]

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.

5
[ 331646-99-2 ]
[ 1262431-81-1 ]

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.

6
[ 331646-99-2 ]
[ 1262431-82-2 ]

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.

7
[ 331646-99-2 ]
[ 1262431-83-3 ]

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.

8
[ 124-38-9 ]
[ 114344-60-4 ]
[ 331646-99-2 ]

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.

9
[ 608-30-0 ]
[ 331646-99-2 ]

References: [1]Organic Letters,2011,vol. 13,p. 676 - 679.

10
[ 20776-51-6 ]
[ 57-13-6 ]
[ 331646-99-2 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 100%	at 200.0℃; for 3.0h;	A mixture of 2-amino-3-bromobenzoic acid (10.8 g, 50 mmol, 1 eq.) and urea (15 g, 250 mmol, 5 eq.) was stirred at 200 C for 3 h, then cooled and poured into ice-water. The solid was collected by filtration, washed with H20 for three times, and dried in vacuo to afford 8-bromoquinazoline-2,4(l -dione as a yellow solid (12.1 g, ca.100% yield).
100%	at 200.0℃; for 3.0h;	[0286] A mixture of 2-amino-3-bromobenzoic acid (10.8 g, 50 mmol, 1 eq.) and urea (15 g, 250 mmol, 5 eq.) was stirred at 200 C for 3 h, then cooled and poured into ice-water. The solid was collected by filtration, washed with H20 for three times and dried in vacuo to afford 8-bromoquinazoline-2,4(1H,3H)-dione as a yellow solid (12.1 g, quant. yield).
	at 100.0℃; for 21.0h;	Step A: A vial containing 2-amino-3-bromobenzoic acid (1.00 g, 4.63 mmol, 1.0 eq.) was heated to 160 C. Urea (2.78 g, 46.29 mmol, 10.0 eq.) was added in portions. After 12 h, more urea (2.78 g, 46.29 mmol, 10.0 eq.) was added in portions. The reaction mixture stirred for an additional 8 h. The mixture was then cooled to 100 C and water (20 mL) was added. The resulting suspension was stirred for 1 h at 100 C before being allowed to cool to room temperature. The light brown solid was then collected by filtration. The crude 8-bromoquinazoline-2,4(lH,3H)-dione was used without further purification (0.883 g, 79% yield). l NMR (400 MHz, (CD3)2SO) delta 10.76 (br s, 2H), 7.93 (d, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H). MS (ESI) m/z = 241.10 (M+H)+. LCMS Ret time (UV 214/254): 0.866 min.

References: [1]Patent: WO2015/27222,2015,A2 .Location in patent: Paragraph 0213.
[2]Patent: WO2016/133935,2016,A1 .Location in patent: Paragraph 0286.
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 1523 - 1540.
[4]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 941 - 946.
[5]Patent: WO2018/212774,2018,A1 .Location in patent: Page/Page column 70.

11
[ 331646-99-2 ]
[ 956100-62-2 ]