98556-31-1|4-Chloro-6-iodoquinazoline| Ambeed

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Quality Control of [ 98556-31-1 ] Purity: 95% SDS Specification

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Product Details of [ 98556-31-1 ]

CAS No. :	98556-31-1
Formula :	C₈H₄ClIN₂
M.W :	290.49
SMILES Code :	ClC1=NC=NC2=CC=C(C=C12)I
MDL No. :	MFCD01862193
InChI Key :	BDAIUOPDSRAOKI-UHFFFAOYSA-N
Pubchem ID :	11173809

Safety of [ 98556-31-1 ]

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

Computational Chemistry of [ 98556-31-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	10
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	57.27
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	25.78 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.26
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	3.15
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.89
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.	2.72
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	3.54
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.91

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.24
Solubility	0.0166 mg/ml ; 0.0000573 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.36
Solubility	0.126 mg/ml ; 0.000435 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	-4.89
Solubility	0.00377 mg/ml ; 0.000013 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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.	-5.84 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<0.0
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)	1.8

Application In Synthesis of [ 98556-31-1 ]

* 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.

Downstream synthetic route of [ 98556-31-1 ]

[ 98556-31-1 ] Synthesis Path-Downstream 1~36

1
[ 16064-08-7 ]
[ 98556-31-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 4.5h;Heating / reflux;	To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2- dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-IODO-QUINAZOLIN-4-OL (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2X50 ml). The combined organic extracts are dried (NA2SO4) and concentrated under reduced pressure to yield 5.2 g (99%) of desired product as a tan solid.
92.7%	With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 1h;Inert atmosphere; Reflux;	3.2 ml of dry anhydrous DMF was added to 10 ml of dry DCE.At the same time, the reaction system was placed in a low-temperature cooling bath and stirred at 0.Then 5.3 ml (60 mmol) of oxalyl chloride was added to 25 ml of dry anhydrous DCE to prepare a solution.The solution was slowly dropped into the appeal reaction system dropwise, kept stirring, and protected with nitrogen throughout.During the addition, a white solid precipitated in the reaction system and the reaction was removed after the dripping.Stir at room temperature for 5 minutes. Then compound 1 (5.0 g 18 mmol) was added to the reaction system.After the addition was complete, the reaction was transferred to an oil bath and the reaction was heated to reflux for 1 hour. Nitrogen protection was maintained throughout the reaction.After 1 hour, the reaction was removed from the oil bath and kept stirring to cool to room temperature.About 100 ml of ice water was added and the mixture was extracted with DCM (100 mL×3). The aqueous layer was separated and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 4.36 g of a light gray solid (yield: 92.7). %).
88%	With triethylamine; trichlorophosphate; In toluene; at 80℃; for 2.5h;Inert atmosphere;	To 6-iodo-quinazolin-4-one (0.54g, 2mmol) in dry toluene (2ml), was added a solution of phosphorus oxychloride (0.37g, 2.4mmol) under nitrogen, triethylamine (0.24 g, 2.4mmol) was added dropwise and the mixture was raised to 80 C stirred for 2.5h. The reaction solution was cooled to 2 C stirred for 1h and filtered. The filter cake was washed with acetone, washed with 1mol/L aqueous sodium hydroxide solution (in 3 ml) then washed with water and acetone and dried in vacuo to give a beige powder (0.5g, 88%).

77%	With thionyl chloride; In N,N-dimethyl-formamide;Reflux;	6-iodo-4(1H)-quinazolinone (10 g, 37 mmol)was weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5mL, 6.5 mmol) were added to give a grey suspension. The mixture was heated to reflux.Heating was continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid precipitated and was collected by filtration to afford 8.6 g (77%) of the title compound.
53%	With trichlorophosphate;	6-Iodoquinazolin-4(3H)-one (1Og, 37 mmol) was refluxed in POCI3 (100 mL) overnight. Then POCI3 was removed in vacuo. The residue was dissolved in CH2Cl2 (500 mL ). The organic phase was washed with water (100 mL) and dried (MgSO4). Then CH2Cl2 was removed in vacuo and 1404-174 was obtained (5.7 g, 53%): LC- MS: 291 [M+l]+, 1H NMR (CDCl3): δ 7.81 (d, J= 9.0 Hz, 1 H), 8.21 (dd, Ji = 9.0 Hz, J2 = 1.8 Hz, I H), 8.65 (d, J= 1.8 Hz, 1 H), 9.06 (s, 1 H).
	With tributyl-amine; trichlorophosphate; In toluene; at 20 - 90℃;Heating / reflux;	Example 1; Preparation of GW572016F; STAGE 1; A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1 eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 700C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. <n="25"/>Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
	With tributyl-amine; trichlorophosphate; In toluene; at 20 - 90℃;Heating / reflux;	A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 7O0C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
	With tributyl-amine; trichlorophosphate; In toluene; at 70 - 80℃; for 2h;Heating / reflux;	A stirred suspension of 3W-6-iodoquinazolin-4-one in toluene (5 vols) is treated with tri-n-butylamine (1.2 equiv.), and then heated to 70-800C. Phosphorous oxychloride (1.1 equiv.) is added and the reaction mixture is then heated to reflux and stirred at this temperature for at least 2 hours. The reaction mixture is then cooled to 55C and toluene (5vol) added followed by 3-chloro-4-[(3-fluorophenyl)rnethyl]oxy}aniline (1.03 equiv.). The reaction mixture is then warmed to 70-900C and stirred for at least 2 hours. The resultant slurry is transferred to a second vessel. The temperature is adjusted to 70-750C and 8 molar aqueous sodium hydroxide solution (2 vols) added over 1 hour, followed by water (6vol.) maintaining the contents at 70-850C. The mixture is stirred at 70-850C for ca. 1 hour and then cooled to 20-250C. The suspension is stirred for ca. 2 hours and the product collected by filtration, and washed successively with water, 0.1 molar aqueous sodium hydroxide, water, and IMS, then dried in vacuo. EPO <DP n="48"/>
	With thionyl chloride; In N,N-dimethyl-formamide;Reflux;	Example 1 Preparation of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodine-quinazolin-4-amine 6-Iodine-3H-quinazolin-4-ketone (100 g) was added into a 2000 mL flask, dissolved in a mixed solvent of thionyl chloride (1000 mL) and N,N-dimethylformamide (20 mL), heated to reflux until the reaction solution is clear and transparent. After thionyl chloride was removed, anhydrous toluene was added to the residues and removed under reduced pressure, and the process of the adding and removing of toluene was repeated again to removed the remained thionyl chloride residues. The intermediate was dissolved in isopropyl alcohol (2000 mL), 3-chloro-4-(3-fluoro-benzyloxy)-aniline hydrochloride was added, and anhydrous K2CO3 (150 g) was added with mechanical stirring before the mixture was heated to reflux over night. The reaction solution was cooled to room temperature overnight, the precipitation was filtered and washed with water for multi-times until the pH of washing solution reached neutral. After drying under vacuum, 95 g of the title product was collected in a pale white solid. m/z M+1+: 506
	With thionyl chloride; for 2h;Reflux;	Example 1 Synthesis of CD 8/CD 19 inhibitors SNX-2-1-165 was synthesized according to the scheme shown in Figure 2. All other compounds were synthesized using similar procedures.
	With tributyl-amine; trichlorophosphate; In toluene; at 20℃;Heating / reflux;	A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq. ) at 20 to 25C, then heated to 90C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 50C and toluene (5vols) added. Compound C (1.03 eq. ) was added as a solid, the slurry was warmed back to 90C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 70C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-70C for 1 hour and then cooled to 20C over 1 hour. The suspension was stirred at 20C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-60C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
	With tributyl-amine; trichlorophosphate; In toluene; at 20℃;Heating / reflux;	A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq. ) at 20 to 25C, then heated to 90C. Phosphorous oxychloride (1.1 eq) was added, the reaction mixture was then heated to reflux.
	With P,P-dichlorophenylphosphine oxide; at 150℃; for 1h;	A mixture of 6-iodoquinazolin-4 (3H)-one (Intermediate 11,100 mg, 0.37 mmol) and phenylphosphonic dichloride (1.5 ML) was heated at 150 C for one h. After cooling the reaction mixture in an ice bath, isopropyl ether was added. The resultant crystalline precipitate was collected by filtration, and was then stirred with saturated aqueous sodium bicarbonate solution. The solution was extracted with three portions of ethyl acetate, and the combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give the crude product. Purification by preparative thin layer chromatography (silica gel, 5% and 10% ethyl acetate/hexanes) afforded the desired product. LC/MS 291 (M+1).

References: [1]Patent: WO2004/46101,2004,A2 .Location in patent: Page 19-20.
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[17]Chemistry and biodiversity,2020,vol. 17.

2
[ 168268-00-6 ]
[ 98556-31-1 ]
[ 231278-23-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691.

3
[ 98556-31-1 ]
[ 70338-47-5 ]
[ 231278-27-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	In isopropyl alcohol; for 3.5h;Reflux;	6-Iodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)amine (0648) The mixture of 4-chloro-6-iodo-quinazoline (366 mg, 1.26 mmol) and 4-O-benzyl-3-trifluoroaniline (405 mg, 1.26 mmol) in isopropanol (12 ml) was heated to reflux for 3.5 hours. Filtered, washed with isopropanol and dried. 535 mg yellow solid was afforded. (yield: 76%). ESI-MS m/z 522 (M+H)+.

References: [1]Patent: US9199973,2015,B2 .Location in patent: Page/Page column 45; 46.
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691.

4
[ 299465-16-0 ]
[ 98556-31-1 ]
6-iodo-4-[5-(3,4,5-trimethoxy-phenyl)-[1,3,4]thiadiazol-2-ylsulfanyl]-quinazoline [ No CAS ]