174565-63-0|7-Nitroquinazoline-2,4(1H,3H)-dione| Ambeed

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Quality Control of [ 174565-63-0 ] Purity: 98% SDS Specification

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Product Details of [ 174565-63-0 ]

CAS No. :	174565-63-0
Formula :	C₈H₅N₃O₄
M.W :	207.14
SMILES Code :	O=C(N1)NC2=C(C=CC([N+]([O-])=O)=C2)C1=O
MDL No. :	MFCD02091151
InChI Key :	FDAQHIHYBBEDQQ-UHFFFAOYSA-N
Pubchem ID :	3398113

Safety of [ 174565-63-0 ]

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

Application In Synthesis of [ 174565-63-0 ]

* 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 [ 174565-63-0 ]

[ 174565-63-0 ] Synthesis Path-Downstream 1~35

1
[ 174565-63-0 ]
[ 59674-85-0 ]

References: [1]Journal of the American Chemical Society,1942,vol. 64,p. 2644,2646.
[2]Organic and Biomolecular Chemistry,2010,vol. 8,p. 5053 - 5055.

2
[ 174565-63-0 ]
[ 129112-65-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 140℃; for 3h;	To a mixture of 7-nitroquinazoline-2,4(lH,3H)-dione (3.0 g, 14.4 mmol) in phosphoryl trichloride (20 mL) was added DIEA (3.7 g, 28.9 mmol) slowly at rt. The reaction mixture was heated to 140C for 3h. Then the reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 5: 1) to afford 2,4-dichloro-7-nitroquinazoline (2.5 g, 71%) as a yellow solid.1HNMR (400 MHz, CDCb): d 8.48-8.49 (m, 2H), 8.86 (s, 1H).
52%	With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 140℃; for 3h;	7-Nitroquinazoline-2,4(1H,3H)-dione (2a, 1.03 g, 5 mmol), DIPEA (1.17 mL, 10 mmol), and POCl3 (5.0 mL) were mixed and refluxed at 140 C for 3 h. The solution was cautiously poured into crushed ice and stirred vigorously. This aqueous mixture was extracted with CH2Cl2, the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crystalline solid was redissolved in CH2Cl2, filtered over a pad of silica using CH2Cl2 as eluent. Removal of the organic solvent gave 3a as gray solid (630 mg, 52% yield, Rf = 0.31 in 1:10 EtOAc/PE). 3a was used for the following reaction without further purification.
	With trichlorophosphate; In 2,3,5-trimethyl-pyridine; water; ethyl acetate; acetonitrile;	b) 18.6 ml (0.204 mol) of phosphorus oxychloride were added to a solution of 3.5 g (0.01 7 mol) of 7-nitro-1,2,3,4-tetrahydroquinazoline-2,4-dione and 6.5 ml (0.051 mol) of collidine in 60 ml of acetonitrile and the mixture was subsequently heated at reflux for 4 hrs. The solvent was removed on a rotary evaporator and the residue was partitioned between 300 ml of water and 300 ml of ethyl acetate. The organic phase was washed with 200 ml of saturated NaHCO3 solution and 2* with 200 ml of saturated sodium chloride solution and finally dried over sodium sulphate. After filtration and concentration the residue was chromatographed over Florisil with methylene chloride as the eluent. 2.46 g (60%) of 2,4-dichloro-7-nitroquinazoline were obtained as yellow crystals; MS: me/e=243, 245 (M+).

	With triethylamine; trichlorophosphate; at 115℃; for 17h;	General procedure: Anthranilic acids (3, 29.1 mmol, 1 eq) and urea (582.8 mmol, 20 eq) were poured into 100 mL round bottom flask. Then, the reaction mixture was heated at 150 oC for 20 h. The reaction was monitored by TLC. After the reaction was completed, it cooled down to room temperature. Then, 60 mL water was poured and the reaction mixture was heated at 100 oC for 1 h. The reaction mixture was cooled in ice bath and the white solid was precipitated. The white solid was filtered and washed with water and hexane. The residue (4, 28.3 mmol, 97%) was dried in vacuo and used next step without further purification. The chemical yield of first reaction was usually around 90%. The compound 4 (28.3 mmol, 1 eq) was dissolved in triethylamine (56.6 mmol, 2 eq). Then, POCl3 (254.5 mmol, 9 eq) was slowly added to the reaction mixture. The reaction mixture was heated at 115 oC for 17 h. The reaction was monitored by TLC. After the completion of the reaction, the reaction solvents were evaporated with toluene several times. The residue was diluted with water and extracted with ethyl acetate several times. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude 5 (25.2 mmol) was used in next step without further purification. The crude 5 (25.2 mmol) was dissolved in 2 N NaOH solution (75.6 mmol, 38 mL, 3 eq) and was stirred at room temperature for 20 h. The reaction mixture was cooled to room temperature. Acetic acid (75.6 mmol, 3 eq) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude 6 (19.4 mmol), which was used in next step without further purification. To a 25 mL round bottom flask were added crude 6 (0.93 mmol), anilines (7, 2.8 mmol, 3 eq), and DMF (3.1 mL). The reaction mixture was stirred at 85 oC for 16 h. The reaction mixture was cooled to room temperature and precipitates were formed. The precipitates were washed with water and hexane thoroughly. The residue (8, 0.88 mmol, 94%) was dried in vacuo. If the precipitates were not formed, the reaction mixture was purified by prep HPLC (Shim-pack PREP-ODS, H2O:CH3CN:CH3OH=40:30:30 to H2O:CH3CN:CH3OH=1:49.5:49.5, flow rate=12 mL/min, 40 oC, λ=254 nm, retention time : 30 min). The chemical yields for each final products are described below.
	With trichlorophosphate; at 0 - 110℃; for 16h;	To a stirred solution of <strong>[174565-63-0]7-nitroquinazoline-2,4(1H,3H)-dione</strong> (10.3 g, 49.76 mmol) in phosphorus oxychloride (48 mL, 497.58 mmol) and N, N-diisopropylethylamine (13 mL, 74.64 mmol) at 0 C and the mixture was heated to 110 C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with crushed ice and stirred for 10 min. The resulting solids were filtered and dried under vacuum to give the desired product. LCMS(m/z) 244.11 [M+H]+.

References: [1]Patent: WO2021/11796,2021,A1 .Location in patent: Paragraph 00226.
[2]European Journal of Medicinal Chemistry,2016,vol. 108,p. 644 - 654.
[3]Journal of the Chemical Society,1948,p. 1759,1765.
[4]Patent: US5688803,1997,A .
[5]Bioorganic and Medicinal Chemistry Letters,2021,vol. 39.
[6]Patent: WO2021/130638,2021,A1 .Location in patent: Paragraph 1054.

3
[ 174565-63-0 ]
[ 76089-18-4 ]

References: [1]Journal of the American Chemical Society,1942,vol. 64,p. 2644,2646.

4
[ 57-13-6 ]
[ 619-17-0 ]
[ 174565-63-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	at 160℃; for 6h;	A mixture of 2-amino-4-nitrobenzoic acid (10.0 g, 55.0 mmol) and urea (33.0 g, 55.0 mmol) was heated to 160 C for 6h. Then the reaction mixture was cooled to 100C and water (60 mL) was added. The solution was stirred for 5 min. The formed precipitate was fdtered off, washed with cold water and further suspended in 0.5N NaOH (50 mL). The mixture was refluxed for 5 min. Then the reaction mixture was cooled to RT and fdtered. The fdtrate was adjusted to pH=2 with cone. HC1. The crude product was fdtered off, washed with MeOFWLO = 1 : 1 (100 mL) and dried in vacuo to give 7-nitroquinazoline-2,4(lH,3H)-dione (10.4 g, 91%) as a yellow solid. Calc’d for C8H5N3O4, 208.0; Found, 208.0
90%	at 160℃; for 6h;	2-Amino-4-nitrobenzoic acid 1a (2.21 g, 10 mmol) and urea (6.0 g, 100 mmol) were stirred at 160 C for 6 h, then cooled to 100 C and water (60 mL) was added. The solution was stirred for 5 min, the formed precipitate was filtered off, washed with cold water and further suspended in 0.5 N NaOH. The mixture was refluxed for 5 min, then cooled to rt. The pH was adjusted to 2 with conc. HCl. Crude 2a was filtered off, washed with MeOH/H2O (1:1), dried in vacuo to give 2a (1.85 g, 90% yield) as light-brown powder. MS (ESI + APCI) m/z: 206.0 [M-H]-.
	at 150℃; for 20h;	General procedure: Anthranilic acids (3, 29.1 mmol, 1 eq) and urea (582.8 mmol, 20 eq) were poured into 100 mL round bottom flask. Then, the reaction mixture was heated at 150 oC for 20 h. The reaction was monitored by TLC. After the reaction was completed, it cooled down to room temperature. Then, 60 mL water was poured and the reaction mixture was heated at 100 oC for 1 h. The reaction mixture was cooled in ice bath and the white solid was precipitated. The white solid was filtered and washed with water and hexane. The residue (4, 28.3 mmol, 97%) was dried in vacuo and used next step without further purification. The chemical yield of first reaction was usually around 90%. The compound 4 (28.3 mmol, 1 eq) was dissolved in triethylamine (56.6 mmol, 2 eq). Then, POCl3 (254.5 mmol, 9 eq) was slowly added to the reaction mixture. The reaction mixture was heated at 115 oC for 17 h. The reaction was monitored by TLC. After the completion of the reaction, the reaction solvents were evaporated with toluene several times. The residue was diluted with water and extracted with ethyl acetate several times. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude 5 (25.2 mmol) was used in next step without further purification. The crude 5 (25.2 mmol) was dissolved in 2 N NaOH solution (75.6 mmol, 38 mL, 3 eq) and was stirred at room temperature for 20 h. The reaction mixture was cooled to room temperature. Acetic acid (75.6 mmol, 3 eq) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude 6 (19.4 mmol), which was used in next step without further purification. To a 25 mL round bottom flask were added crude 6 (0.93 mmol), anilines (7, 2.8 mmol, 3 eq), and DMF (3.1 mL). The reaction mixture was stirred at 85 oC for 16 h. The reaction mixture was cooled to room temperature and precipitates were formed. The precipitates were washed with water and hexane thoroughly. The residue (8, 0.88 mmol, 94%) was dried in vacuo. If the precipitates were not formed, the reaction mixture was purified by prep HPLC (Shim-pack PREP-ODS, H2O:CH3CN:CH3OH=40:30:30 to H2O:CH3CN:CH3OH=1:49.5:49.5, flow rate=12 mL/min, 40 oC, λ=254 nm, retention time : 30 min). The chemical yields for each final products are described below.

at 150℃; for 16h;

A mixture of 2-amino-4-nitrobenzoic acid (10 g, 54.94 mmol) and urea (32.96 g, 549.45 mmol) was heated to 150 C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-water and stirred for 10 min. The resulting solids were collected and triturated with glacial acetic acid to give the desired product. LCMS(m/z) 208.14 [M+H]+.

References: [1]Patent: WO2021/11796,2021,A1 .Location in patent: Paragraph 00225.
[2]European Journal of Medicinal Chemistry,2016,vol. 108,p. 644 - 654.
[3]Journal of the Chemical Society,1948,p. 1759,1765.
[4]Organic and Biomolecular Chemistry,2010,vol. 8,p. 5053 - 5055.
[5]Bioorganic and Medicinal Chemistry Letters,2021,vol. 39.
[6]Patent: WO2021/130638,2021,A1 .Location in patent: Paragraph 1053.

5
7-nitro-2-thioxo-2,3-dihydroquinazolin-4(1H)-one [ No CAS ]
[ 174565-63-0 ]

References: [1]Chemistry of Heterocyclic Compounds,2006,vol. 42,p. 540 - 545.

6
[ 619-17-0 ]
[ 174565-63-0 ]

Yield	Reaction Conditions	Operation in experiment
	With urea; In methanol;	a) A mixture of 5 g (0.027 mol) of 2-amino-4-nitrobenzoic acid and 16.5 g (0.27 mol) of urea was heated to 160 C. for 2 hrs. and at 180 C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. 4.8 g (80%) of 7-nitro-1,2,3,4-tetrahydro-quinazoline-2,4-dione were obtained as a white solid; MS: me/e=207 (M+).

References: [1]Chemistry of Heterocyclic Compounds,2006,vol. 42,p. 540 - 545.
[2]Patent: US5688803,1997,A .
[3]Journal of Chemical Research,2011,vol. 35,p. 129 - 132.

7
[ 174565-63-0 ]
[ 174565-80-1 ]

Yield	Reaction Conditions	Operation in experiment
		a) 10 g (48.3 mmol) of <strong>[174565-63-0]7-nitro-1,2,3,4-tetrahydro-quinazoline-2,4-dione</strong> were added portionwise at 0 C. to 32 ml of fuming nitric acid. Thereafter, the mixture was stirred at room temperature for a further 5 hrs. The reaction mixture was poured on to ice, the precipitate was filtered off under suction and washed with 65% nitric acid, dilute nitric acid and finally with water. 7.15 g (59%) of 6,7-dinitro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as a yellow powder; MS: me/e=252 (M+).

References: [1]Patent: US5688803,1997,A .

8
[ 174565-63-0 ]
[ 32618-85-2 ]
[ 100-39-0 ]
[ 1032373-44-6 ]
[ 1032373-45-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	SynthesisPeptidomimetics 37-44 were synthesized via solid phase peptide synthesis, using Suzuki couplings employing various boronic acids and aryl bromides. Intermediates display hydrophobic substituents from the aromatic spacer (Abz). The simple quinazoline scaffolds derived from commercially available starting materials. The synthesis of the quinazolines cores 45a-b was accomplished by the cyclization of 4-nitroanthranilic acid by the reaction with sodium isocyanate or cyclization employing a carbon dioxide atmosphere with catalytic DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) from 4- and 5-nitro precursors respectively Figure 10. Alkylation was followed by reduction of the nitro group followed by coupling with A- nitrobenzoyl chloride via anilide formation to provide 48a-b. Reduction to the aniline, coupling with AcArg(Pmc)-OH, and deprotection of the guanidine protecting group afforded 50a-b.A convergent synthesis using methyl-4-amino-2-bromobenzoate or methyl-4-aminobenzoate and 4-nitroaniline created non-peptidic inhibitors 56aa-ci, as seen in Figure 13. Suzuki coupling of the bromoaniline with the corresponding boronic acid, employing PdCI2(dppf) as a catalyst, created compounds 51a followed by reductive amination utilizing N-Boc- aminoacetaldehyde produced compounds 52a-c. A series of deprotections followed by guanidinylation of the resulting amine afforded the N-terminal portions of the inhibitor 53a-c. The C-terminal hydrophobic portion of the molecule was synthesized via alkylation of A- nitroaniline with the corresponding bromide and subsequent reduction of the nitro group utilizing tin (II) chloride, producing compounds 55a-i. Coupling of compounds 53a-c and 55a- i followed by Boc deprotection under acidic conditions produced inhibitors 56aa-ci. Inhibitors64a-b were derived from a similar synthesis, but in place of the reductive amination step, 48c was reacted with Boc-Gly-OH to provide the amide intermediate compound 62 which was manipulated in a similar manner to provide inhibitors 64a-b, seen in Figure 16.The synthesis of inhibitors 57aa-fa was designed to employ a late stage Suzuki coupling to provide faster access to a number of derivatives at the R1 position, while keeping R2 as a <n="13"/>benzyl substituent, see Figure 15. Commercially available methyl-4-amino-3-bromobenzoate was saponified under basic conditions followed by amide bond formation with compound 55a to provide compound 59a. This intermediate was then reacted with different boronic acid derivatives PdCI2(dppf) as a catalyst to provide 60aa-fa. A series of functional group transformations provided inhibitors 57aa-fa. The indole scaffold was readily derived from commercially available 4-iodoaniline and Boc- GIy-OH, which were reacted to form iodo-amide compound 65, seen in Figure 17. Sonagashira cross-coupling of compound 65 and ethynyl-trimethyl-silane (TMS-acetylene) followed by removal of the silyl protecting group afforded terminal alkyne compound 66. A consecutive Sonagashira cross-coupling with 2-iodo-4-nitroaniline followed by cycloisomerization employing catalytic copper (II) acetate41 afforded indole scaffold compound 68. Reduction of the nitro to the amine followed by alkylation with the cooresponding bromide provided compound 70a-b. A series of functional group transformations, similar to the reactions depicted in Figures 10 and 13, provided inhibitors 71a-b. It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween. Now that the invention has been described,

References: [1]Patent: WO2008/70823,2008,A2 .Location in patent: Page/Page column 4-5; 10-11; 6/14.

9
[ 917-61-3 ]
[ 619-17-0 ]
[ 174565-63-0 ]

Yield	Reaction Conditions	Operation in experiment
		SynthesisPeptidomimetics 37-44 were synthesized via solid phase peptide synthesis, using Suzuki couplings employing various boronic acids and aryl bromides. Intermediates display hydrophobic substituents from the aromatic spacer (Abz). The simple quinazoline scaffolds derived from commercially available starting materials. The synthesis of the quinazolines cores 45a-b was accomplished by the cyclization of 4-nitroanthranilic acid by the reaction with sodium isocyanate or cyclization employing a carbon dioxide atmosphere with catalytic DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) from 4- and 5-nitro precursors respectively Figure 10. Alkylation was followed by reduction of the nitro group followed by coupling with A- nitrobenzoyl chloride via anilide formation to provide 48a-b. Reduction to the aniline, coupling with AcArg(Pmc)-OH, and deprotection of the guanidine protecting group afforded 50a-b.A convergent synthesis using methyl-4-amino-2-bromobenzoate or methyl-4-aminobenzoate and 4-nitroaniline created non-peptidic inhibitors 56aa-ci, as seen in Figure 13. Suzuki coupling of the bromoaniline with the corresponding boronic acid, employing PdCI2(dppf) as a catalyst, created compounds 51a followed by reductive amination utilizing N-Boc- aminoacetaldehyde produced compounds 52a-c. A series of deprotections followed by guanidinylation of the resulting amine afforded the N-terminal portions of the inhibitor 53a-c. The C-terminal hydrophobic portion of the molecule was synthesized via alkylation of A- nitroaniline with the corresponding bromide and subsequent reduction of the nitro group utilizing tin (II) chloride, producing compounds 55a-i. Coupling of compounds 53a-c and 55a- i followed by Boc deprotection under acidic conditions produced inhibitors 56aa-ci. Inhibitors64a-b were derived from a similar synthesis, but in place of the reductive amination step, 48c was reacted with Boc-Gly-OH to provide the amide intermediate compound 62 which was manipulated in a similar manner to provide inhibitors 64a-b, seen in Figure 16.The synthesis of inhibitors 57aa-fa was designed to employ a late stage Suzuki coupling to provide faster access to a number of derivatives at the R1 position, while keeping R2 as a <n="13"/>benzyl substituent, see Figure 15. Commercially available methyl-4-amino-3-bromobenzoate was saponified under basic conditions followed by amide bond formation with compound 55a to provide compound 59a. This intermediate was then reacted with different boronic acid derivatives PdCI2(dppf) as a catalyst to provide 60aa-fa. A series of functional group transformations provided inhibitors 57aa-fa. The indole scaffold was readily derived from commercially available 4-iodoaniline and Boc- GIy-OH, which were reacted to form iodo-amide compound 65, seen in Figure 17. Sonagashira cross-coupling of compound 65 and ethynyl-trimethyl-silane (TMS-acetylene) followed by removal of the silyl protecting group afforded terminal alkyne compound 66. A consecutive Sonagashira cross-coupling with 2-iodo-4-nitroaniline followed by cycloisomerization employing catalytic copper (II) acetate41 afforded indole scaffold compound 68. Reduction of the nitro to the amine followed by alkylation with the cooresponding bromide provided compound 70a-b. A series of functional group transformations, similar to the reactions depicted in Figures 10 and 13, provided inhibitors 71a-b. It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween. Now that the invention has been described,

References: [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1764 - 1771.
[2]Patent: WO2008/70823,2008,A2 .Location in patent: Page/Page column 4-5; 10-11; 6/14.

10
[ 174565-63-0 ]
[ 100-39-0 ]
[ 1032373-44-6 ]

References: [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1764 - 1771.

11
[ 610-30-0 ]
[ 174565-63-0 ]

References: [1]Journal of Chemical Research,2011,vol. 35,p. 129 - 132.

12
[ 610-68-4 ]
[ 174565-63-0 ]

References: [1]Journal of Chemical Research,2011,vol. 35,p. 129 - 132.

13
[ 1029420-40-3 ]
[ 174565-63-0 ]