20872-93-9|7-Nitroquinazolin-4(3H)-one| Ambeed

Structure of 20872-93-9

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Quality Control of [ 20872-93-9 ] Purity: 95% SDS Specification

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Product Details of [ 20872-93-9 ]

CAS No. :	20872-93-9
Formula :	C₈H₅N₃O₃
M.W :	191.14
SMILES Code :	O=C1NC=NC2=C1C=CC([N+]([O-])=O)=C2
MDL No. :	MFCD00089998
InChI Key :	LPCJURLBTXOJHS-UHFFFAOYSA-N
Pubchem ID :	86222800

Safety of [ 20872-93-9 ]

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

Computational Chemistry of [ 20872-93-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	10
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	51.19
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	91.57 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.82
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	0.6
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.83
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.	0.11
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	-0.12
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.45

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.87
Solubility	2.6 mg/ml ; 0.0136 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.1
Solubility	1.53 mg/ml ; 0.008 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	-2.62
Solubility	0.46 mg/ml ; 0.0024 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	No
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.	-7.04 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	2.0 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)	1.96

Application In Synthesis of [ 20872-93-9 ]

* 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.

Upstream synthesis route of [ 20872-93-9 ]
Downstream synthetic route of [ 20872-93-9 ]

[ 20872-93-9 ] Synthesis Path-Upstream 1~8

1
[ 77287-34-4 ]
[ 619-17-0 ]
[ 20872-93-9 ]

Yield	Reaction Conditions	Operation in experiment
86.6%	at 150℃; for 16 h;	2-amino-4-nitrobenzoic acid (7.28g, 40.0mmol) and ammonium formate (3.78g, 60.0mmol) were added to 1OmL of formamide, heated to 150 ° C, incubated 16h, cooled to room temperature, Precipitation of solid,Filtered, washed with isopropanol and dried to give 6.62 g of 86 mg as a brown needles of 7-nitro-3H-quinazolin-4-one in 86.6percent yield.
83%	at 140℃;	General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO₄ and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO₄ and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl₂*2H₂O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO₄ and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO₄ and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.

References: [1] Cell Chemical Biology, 2017, vol. 24, # 12, p. 1490 - 11,1500.
[2] Journal of the American Chemical Society, 2016, vol. 138, # 33, p. 10554 - 10560.
[3] Patent: US2017/174638, 2017, A1, . Location in patent: Paragraph 0045.
[4] Tetrahedron Letters, 2003, vol. 44, # 24, p. 4455 - 4458.
[5] Patent: CN103382182, 2016, B, . Location in patent: Paragraph 0113; 0115-0117.
[6] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273.
[7] Journal of the American Chemical Society, 1908, vol. 30, p. 810.
[8] Yakugaku Zasshi, 1942, vol. 62, p. 66,68; dtsch. Ref. S. 24[9] Chem.Abstr., 1951, p. 1580.
[10] Patent: WO2014/120346, 2014, A1, . Location in patent: Page/Page column 33.
[11] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502.
[12] Chemistry and Biodiversity, 2018, vol. 15, # 6, .

2
[ 3473-63-0 ]
[ 619-17-0 ]
[ 20872-93-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	at 130℃; for 18 h;	A mixture of 2-amino-4-nitrobenzoic acid (10.0 g, 54.93 mmol) was refluxed at 130° C. for 18 h in methoxyethanol (50 mL) and formamidine acetate (11.43 g, 109.81 mmol). The clear reaction mixture was cooled to room-temperature to form a yellowish precipitant. The solvent was removed under vacuum, and the precipitant was washed several times with aqueous ammonia (0.01 M). The solid was dried in vacuo to yield 8.9 g (84percent) of a light yellow powder. ¹H NMR Data: dmso-d₆-ppm (δ); 12.68 (1H), 8.37 (d, 1H), 8.33 (d, 1H), 8.26 (1H) and 8.23 (dd, 1H).

References: [1] Patent: US2016/376298, 2016, A1, . Location in patent: Paragraph 0220.
[2] Spectroscopy Letters, 2012, vol. 45, # 7, p. 530 - 540,11.
[3] Patent: CN103360382, 2016, B, . Location in patent: Paragraph 0228; 0244; 0245.

3
[ 6313-33-3 ]
[ 619-17-0 ]
[ 20872-93-9 ]

Yield	Reaction Conditions	Operation in experiment
44%	at 200℃; for 0.5 h;	Example 8Synthesis of 7-aminoquinazolin-4-one 4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar and pestle to produce a fine, intimate mixture. The mixture was placed in a 250 mL round-bottom flask, and spread evenly over the surface. The flask was placed in an oilbath at 200° C. The solid underwent a color change, and a distillate was seen on the side of flask, but did not really melt. After 30 min the flask was removed from the heating bath. 0.3M sodium hydroxide solution (150 mL) was added to the cooled flask, the black solid mass was broken up with a spatula, and stirred for 1 h. The solid was filtered off and washed with water. The filtrate was discarded. The black solid was suspended in dichloromethane/methanol (10:1) and filtered through a plug of silica, eluting with the same solvent until no more product came off. The material was one spot by TLC, plus black baseline material, but was poorly soluble, so a large volume of solvent was needed.The filtrate was evaporated to dryness and the solid residue triturated with a little methanol and filtered to give 7-nitroquinazoline-4-one (4.65 g, 44percent).

References: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3860 - 3873.
[2] Patent: US2008/161297, 2008, A1, . Location in patent: Page/Page column 46.
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 11, p. 3235 - 3239.

4
[ 64392-62-7 ]
[ 619-17-0 ]
[ 20872-93-9 ]

References: [1] Journal of Organic Chemistry, 1986, vol. 51, # 5, p. 616 - 620.

5
[ 31930-18-4 ]
[ 149-73-5 ]
[ 20872-93-9 ]

References: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 545 - 548.
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391.

6
[ 619-17-0 ]
[ 20872-93-9 ]

References: [1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391.

7
[ 19815-14-6 ]
[ 20872-93-9 ]

References: [1] Journal of the Chemical Society, 1948, p. 360,364.
[2] Journal of the Chemical Society, 1950, p. 1104,1111.
[3] Journal of the Chemical Society, 1948, p. 360,364.

8
[ 19815-17-9 ]
[ 20872-93-9 ]

References: [1] Journal of the Chemical Society, 1950, p. 1104,1111.

[ 20872-93-9 ] Synthesis Path-Downstream 1~35

1
[ 19815-17-9 ]
[ 20872-93-9 ]

References: [1]Journal of the Chemical Society,1950,p. 1104,1111.

2
[ 19815-14-6 ]
[ 20872-93-9 ]

References: [1]Journal of the Chemical Society,1948,p. 360,364.
[2]Journal of the Chemical Society,1948,p. 360,364.

3
[ 20872-93-9 ]
[ 77-78-1 ]
[ 874497-86-6 ]

References: [1]Journal of the Chemical Society,1948,p. 360,364.

4
[ 20872-93-9 ]
[ 90004-09-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With stannous chloride dihydrate; In ethyl acetate; for 8h;Reflux;	General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2·2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 × 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
54%	With hydrogen;palladium 10% on activated carbon; In methanol; N,N-dimethyl-formamide; under 2585.81 Torr; for 21h;	A suspension of 7-nitroquinazolinone (5.2 g, 22.7 mmol) in DMF (150 mL) and methanol (100 mL) was hydrogenated over 10% palladium on carbon (600 mg) in a Parr shaker at 50 psi. The starting material was consumed in 3 h, but hydrogenation was continued for 18 h to ensure complete reaction. The mixture was filtered through diatomaceous earth, washing with methanol/DMF 2:1 until all of the product was eluted. The filtrate was evaporated to dryness. The solid residue was stirred with methanol (20 mL) for 1 h, filtered, washed with methanol and dried to give the crude amine (3.88 g), which contained a minor component (ca. 10%). The crude product was dissolved in 2 N HCl (100 mL), with warming, and the resulting solution was evaporated to dryness to give the hydrochloride salt. The salt was dissolved in boiling water (30 mL) and ethanol (30 mL) was added. The solvent was boiled down to 50 mL. The hydrochloride crystallized on cooling. The crystals were filtered, washed with a little ethanol and dried to give the pure salt (3.02 g). The salt was dissolved in water (30 mL) with warming to 65 C. in an oil bath. Ammonium hydroxide was added dropwise, causing immediate precipitation of the free base. The flask was cooled in ice, the crystals filtered, washed with water and dried to give the title compound (2.35 g, 54%).

References: [1]Tetrahedron Letters,2003,vol. 44,p. 4455 - 4458.
[2]European Journal of Medicinal Chemistry,2012,vol. 50,p. 264 - 273.
[3]Patent: US2008/161297,2008,A1 .Location in patent: Page/Page column 46; 47.
[4]Journal of the American Chemical Society,1952,vol. 74,p. 1863.
[5]Journal of Organic Chemistry,1952,vol. 17,p. 149,153.
[6]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3235 - 3239.

5
[ 20872-93-9 ]
[ 19815-17-9 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; N,N-dimethyl-formamide;Reflux;	Step B: 4-Chloro-7-nitroquinazoline To a solution of <strong>[20872-93-9]7-nitroquinazolin-4(3H)-one</strong> (9.14g, 47.8mmol) thionyl chloride (90 mL) was added DMF (2 mL) and the mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, and evaporated to dryness to provide 4-chloro-7-nitroquinazoline. LCMS calc. = 210.01 ; found = 210.06 (M+H)+.
19 g	With thionyl chloride; In N,N-dimethyl-formamide;Reflux;	Take 19.1g (0.1mol) of 7-nitro - -quinazolinone in three 250mL flask, was added dropwise slowly with stirring 60mL freshly distilled DMF containing 2 drops of S0C12, After the addition the reaction was refluxed, the reaction is monitored by TLC process after completion of the reaction, evaporated under reduced pressure excess S0C12, the residue refrigerated ether (5 X20mL) to give the crude product was washed, crude product was recrystallized from ethyl acetate and petroleum ether to give the intermediate compound 7-nitro-4-chloroquinazoline 19.0g, yield white needle crystals yield.: 90.6%, m.p: 150-151C, 1 HNMR (CDCl 3, 400MHz) delta: 8.55 (s, 2H, Ph-H), 8.98 (s, 1H, Ph-H), 9.23 (s, 1H, Ar-H); IR (KBr) nu: 3057, 2959, 1528, 1469, 1357, 805, 743.
	With thionyl chloride; In N,N-dimethyl-formamide; for 1h;Reflux;	A solution of 7-nitro-311-quinazolin-4-one (2.25g, 11.8mmol) was added to 23ml SOCl2 solution, 0.2 mL of DMF and stirred for 1 h under reflux. The reaction was quenched, cooled to room temperature and excess S0C12 evaporated to give 7-nitro-4-chloroquinazoline as a yellow solid.The resulting yellow solid was triturated with 10 mL of petroleum ether,The petroleum ether was distilled off under reduced pressure, and the petroleum ether was repeatedly added thereto twice,To remove the residual S0C12 to give a yellow solid.Aniline (1.31 g, 14.1 mmol) and 37 mL of isopropyl alcohol were added to the above yellow solid without stirring, and the mixture was stirred under reflux for 1.5 h. Solid precipitated and cooled, Filtered, washed with isopropanol and dried to give 1.87 g of 7-nitro-4-anilinoquinazoline as a yellow solid in a yield of59.7%

3.5 g

With thionyl chloride; N,N-dimethyl-formamide; at 110℃; for 0.3h;

[20872-93-9]7-nitroquinazolin-4(3H)-one (20.93 mmol) was suspended in 35 mL of thionyl chloride with a catalytic amount of DMF (3 drops). The mixture was refluxed at 110 C. for approximately 3 hrs until the solution turned clear. The SOCl2 was removed under reduced pressure and then dry benzene was added. The mixture was again reduced under pressure to remove all traces of SOCl2. The crude solid was dissolved in dichloromethane (CH2Cl2). The solution was treated by Na2CO3 carefully until the solution reached pH 7-8. The solution was extracted with dichloromethane (CH2Cl2) and dried over Na2SO4. The solvent was removed under reduced pressure to give the 4-chloro-7-nitroquinazoline (3.5 gram; 16.74 mmol).

References: [1]Journal of the American Chemical Society,2016,vol. 138,p. 10554 - 10560.
[2]Molecular Pharmaceutics,2019,vol. 16,p. 4260 - 4273.
[3]Patent: US2017/174638,2017,A1 .Location in patent: Paragraph 0045.
[4]Spectroscopy Letters,2012,vol. 45,p. 530 - 540,11.
[5]Patent: US1880447,1929, .
[6]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 545 - 548.
[7]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 383 - 391.
[8]Patent: WO2014/120346,2014,A1 .Location in patent: Page/Page column 34.
[9]Patent: CN103360382,2016,B .Location in patent: Paragraph 0228; 0246; 0247.
[10]Patent: CN103382182,2016,B .Location in patent: Paragraph 0113; 0115; 0118; 0119.
[11]Patent: US2016/376298,2016,A1 .Location in patent: Paragraph 0223.

6
[ 77287-34-4 ]
[ 619-17-0 ]
[ 20872-93-9 ]

Yield	Reaction Conditions	Operation in experiment
86.6%	With ammonium formate; at 150℃; for 16h;	2-amino-4-nitrobenzoic acid (7.28g, 40.0mmol) and ammonium formate (3.78g, 60.0mmol) were added to 1OmL of formamide, heated to 150 C, incubated 16h, cooled to room temperature, Precipitation of solid,Filtered, washed with isopropanol and dried to give 6.62 g of 86 mg as a brown needles of 7-nitro-3H-quinazolin-4-one in 86.6% yield.
83%	at 140℃;	General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2·2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 × 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
	at 150℃; for 1h;Microwave irradiation;	Step A: 7-nitroquinazolin-4(3H)-one A mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 82 mmol) and formamide (8 mL, 201.5 mmol) in a microwave reaction vessel was heated in a microwave reactor at 150 C for 1 h. The resulting slurry was cooled to room temperature, stirred with aqueous NaHC03, filtered and the solid was washed with water and Et20 then vacuum dried to provide 7-nitroquinazolin-4(3H)-one as a dark brown solid. LCMS calc. = 192.03; found = 192.16 (M+H)+.

	at 130 - 135℃; for 4h;	General procedure: Compound 18 was prepared accordingto the procedure previously reported.39 A mixture of anthranilicacid 11 (0.1 mol) and formamide (18 g, 0.4 mol) was heated at130-135 C. After the mixture had been stirred for 4 h, water(40 mL) was added. The reaction mixture was cooled to 60 C,and water (20 mL) was added to the mixture. After the mixturehad been stirred for 30 min, the precipitated product wasfiltered off with suction. The crude products were recrystallizedwith ethanol to give compound 18 in yields of 80-95%.
	at 120℃;	General procedure: The mixtures of anthranilic acid or respective 5-substituted-2-aminobenzoicacid (1) (1 mmol) and an excess of formamide (10 mmol) in around-bottom flask were heated at 120 C with stirring for 3-5 h. Thereaction was checked by TLC. After the starting materials completelydisappeared, the resulting mixtures were cooled to room temperatureand then poured into ice-cold water. The light or dark brown precipitateswere formed. The precipitates were filtered and washed threetimes with water (20 mL each) and dried to give quinazoline-4(3H)-onederivatives (2). These intermediates were used for the next step withoutfurther purification.

References: [1]Cell Chemical Biology,2017,vol. 24,p. 1490 - 11,1500.
[2]Journal of the American Chemical Society,2016,vol. 138,p. 10554 - 10560.
[3]Patent: US2017/174638,2017,A1 .Location in patent: Paragraph 0045.
[4]Tetrahedron Letters,2003,vol. 44,p. 4455 - 4458.
[5]Patent: CN103382182,2016,B .Location in patent: Paragraph 0113; 0115-0117.
[6]European Journal of Medicinal Chemistry,2012,vol. 50,p. 264 - 273.
[7]Journal of the American Chemical Society,1908,vol. 30,p. 810.
[8]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1942,vol. 62,p. 66,68; dtsch. Ref. S. 24.
Chem.Abstr.,1951,p. 1580.
[9]Patent: WO2014/120346,2014,A1 .Location in patent: Page/Page column 33.
[10]Biochemistry,2017,vol. 56,p. 6491 - 6502.
[11]Chemistry and biodiversity,2018,vol. 15.
[12]Chemistry and biodiversity,2019,vol. 16.
[13]Journal of Molecular Structure,2020,vol. 1200.
[14]Bioorganic Chemistry,2019,vol. 92.

7
[ 64392-62-7 ]
[ 619-17-0 ]
[ 20872-93-9 ]

References: [1]Journal of Organic Chemistry,1986,vol. 51,p. 616 - 620.

8
[ 20872-93-9 ]
[ 99-81-0 ]
7-Nitro-3-[2-(4-nitro-phenyl)-2-oxo-ethyl]-3H-quinazolin-4-one [ No CAS ]

References: [1]Acta Poloniae Pharmaceutica,1994,vol. 51,p. 249 - 250.

9
[ 20872-93-9 ]
[ 536-38-9 ]
3-(4'-chlorophenacyl)-7-nitro-quinazolin-4(3H)-one [ No CAS ]

References: [1]Acta Poloniae Pharmaceutica,1994,vol. 51,p. 249 - 250.

10
[ 20872-93-9 ]
[ 99-73-0 ]
3-[2-(4-Bromo-phenyl)-2-oxo-ethyl]-7-nitro-3H-quinazolin-4-one [ No CAS ]

References: [1]Acta Poloniae Pharmaceutica,1994,vol. 51,p. 249 - 250.

11
[ 20872-93-9 ]
[ 31827-94-8 ]
3-[2-(4-Iodo-phenyl)-2-oxo-ethyl]-7-nitro-3H-quinazolin-4-one [ No CAS ]

References: [1]Acta Poloniae Pharmaceutica,1994,vol. 51,p. 249 - 250.

12
[ 2969-81-5 ]
[ 20872-93-9 ]
[ 247573-23-5 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3860 - 3873.

13
[ 6313-33-3 ]
[ 619-17-0 ]
[ 20872-93-9 ]

Yield	Reaction Conditions	Operation in experiment
44%	at 200℃; for 0.5h;	Example 8Synthesis of 7-aminoquinazolin-4-one 4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar and pestle to produce a fine, intimate mixture. The mixture was placed in a 250 mL round-bottom flask, and spread evenly over the surface. The flask was placed in an oilbath at 200 C. The solid underwent a color change, and a distillate was seen on the side of flask, but did not really melt. After 30 min the flask was removed from the heating bath. 0.3M sodium hydroxide solution (150 mL) was added to the cooled flask, the black solid mass was broken up with a spatula, and stirred for 1 h. The solid was filtered off and washed with water. The filtrate was discarded. The black solid was suspended in dichloromethane/methanol (10:1) and filtered through a plug of silica, eluting with the same solvent until no more product came off. The material was one spot by TLC, plus black baseline material, but was poorly soluble, so a large volume of solvent was needed.The filtrate was evaporated to dryness and the solid residue triturated with a little methanol and filtered to give 7-nitroquinazoline-4-one (4.65 g, 44%).

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3860 - 3873.
[2]Patent: US2008/161297,2008,A1 .Location in patent: Page/Page column 46.
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3235 - 3239.

Yield	Reaction Conditions	Operation in experiment
90%	With ammonium hydroxide; palladium dichloride; at 90℃; for 0.166667h;Microwave irradiation;	General procedure: (1) adding palladium chloride 0.2 mmol to the microwave reaction tube,2-iodobenzoic acid 1 mmol,Hydrogen cyanide1.2 mmol and 2 ml 25-28% ammoniaWater, then at 120w,The reaction was carried out at 90 C for 10 min.The product was purified by column chromatography to give a white solid.The yield was 96%.(2) The 2-iodobenzoic acid in (1) was replaced with 2-bromobenzoic acid in a yield of 94%.
86%	With ammonium hydroxide; palladium dichloride; at 90℃; for 0.166667h;Microwave irradiation; Green chemistry;	General procedure: (1) Adding 0.2 mmol of palladium chloride and 1 mmol of 2-iodobenzamide to the microwave reaction tube. 1.2 mmol of hydrogen cyanide 2 ml of ammonia water, then reacted at 120 w, 90 C for 10 minutes. The product was extracted with ethyl acetate and concentrated under reduced pressure, The product was purified by column chromatography to give a white solid. The yield was 96%. (2) The 2-iodobenzamide in (1) was replaced with 2-bromobenzamide in a yield of 94%.
86%	With ammonium hydroxide; palladium dichloride; at 90℃; for 0.166667h;Microwave irradiation; Green chemistry;	General procedure: (1) Adding 0.2 mmol of palladium chloride and 1 mmol of 2-iodobenzamide to the microwave reaction tube. 1.2 mmol of hydrogen cyanide 2 ml of ammonia water, then reacted at 120 w, 90 C for 10 minutes. The product was extracted with ethyl acetate and concentrated under reduced pressure, The product was purified by column chromatography to give a white solid. The yield was 96%. (2) The 2-iodobenzamide in (1) was replaced with 2-bromobenzamide in a yield of 94%.

86%	With ammonium hydroxide; palladium dichloride; at 90℃; for 0.166667h;Microwave irradiation;	General procedure: (1) adding palladium chloride 0.2 mmol to the microwave reaction tube,2-iodobenzoic acid 1 mmol,Hydrogen cyanide1.2 mmol and 2 ml 25-28% ammoniaWater, then at 120w,The reaction was carried out at 90 C for 10 min.The product was purified by column chromatography to give a white solid.The yield was 96%.(2) The 2-iodobenzoic acid in (1) was replaced with 2-bromobenzoic acid in a yield of 94%.
82%	With copper 8-hydroxyquinolinate; sodium hydroxide; In water; at 100℃; for 0.5h;Microwave irradiation;	General procedure: 1 mmol of 2-iodo-5-methylbenzoic acid, 1 mmol of formamidine hydrochloride, and 8-quinolinolato copper (B ) 0.05 mmol, 1 mmol of sodium hydroxide and 3 mL of water. Placed in the microwave reactor, the microwave reactor at 150 W power heating 100 C to 30 minutes, cooled to room temperature. The product was extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by column chromatography to give a white solid in 92% yield.
	at 120℃; for 6h;	General procedure: Excess formamide (2 mL) solution containing each 2-aminobenzophosphoric acid (1a-i) (1 mmol) was stirred at 120 C. for 6 hours. After stirring was complete, the resulting mixture was cooled and poured into ice cold water (20 mL). NaHCO 35% solution was added gradually to adjust the pH to 8, thereby forming a white solid. The solid was filtered and dried to give quinazolineone derivative 2, which was used in the next step without further purification. To each solution of DMF (3 mL) containing quinazoline source 2 was added K 2 CO 3 (165.5 mg, 1.2 mmol). The resulting mixture was stirred for 30 min at 60 C., then a catalytic amount of KI (8.3 mg, 0.05 mmol) was added. After stirring for an additional 15 minutes, methyl 7-bromobenzoate or methyl 7-bromooctanoate (1 mmol) was added. The reaction mixture was stirred again at 60 C. for 3 hours until the reaction was complete. The resulting mixture was poured into 10 ml of water, neutralized with 5% HCl and extracted with DCM (3 × 15 mL). The organic layer was collected and filtered over anhydrous Na 2 SO 4. The solvent was removed under reduced pressure to yield intermediate esters 3, 4 as a yellow liquid. Each intermediate ester 3a-i, 4a-i was then dissolved in DMF and hydroxylamine.HCl (685 mg, 10 mmol) was added, followed by the dropwise addition of a solution of NaOH (400 mg in 1 mL of water). . Until the reaction was complete, the mixture was poured into ice cold water, neutralized to pH-7, and acidified by dropwise addition of 5% HCl solution to induce maximum precipitation. The precipitate was filtered, dried and recrystallized with methanol to give the desired compounds 5a-i, 6a-i.

16
[ 31930-18-4 ]
[ 149-73-5 ]
[ 20872-93-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 545 - 548.
[2]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 383 - 391.

17
[ 20872-93-9 ]
[ 100-39-0 ]
[ 591755-13-4 ]

References: [1]Tetrahedron Letters,2003,vol. 44,p. 4455 - 4458.
[2]Journal of Molecular Structure,2020,vol. 1200.

18
[ 20872-93-9 ]
7H-[1,3]thiazolo[4,5-h]quinazolin-6-one [ No CAS ]

References: [1]Tetrahedron Letters,2003,vol. 44,p. 4455 - 4458.
[2]Tetrahedron Letters,2003,vol. 44,p. 4455 - 4458.

19
[ 20872-93-9 ]
[ 591755-15-6 ]

References: [1]Tetrahedron Letters,2003,vol. 44,p. 4455 - 4458.
[2]Journal of Molecular Structure,2020,vol. 1200.

20
[ 20872-93-9 ]
7-(4-chloro-[1,2,3]dithiazol-5-ylideneamino)-3H-quinazolin-4-one [ No CAS ]