1218-69-5|2-(2-Hydroxyphenyl)-4H-benzo[e][1,3]oxazin-4-one| Ambeed

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Quality Control of [ 1218-69-5 ] Purity: 98% SDS Specification

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Product Details of [ 1218-69-5 ]

CAS No. :	1218-69-5
Formula :	C₁₄H₉NO₃
M.W :	239.23
SMILES Code :	OC1=C(C=CC=C1)C1=NC(=O)C2=C(O1)C=CC=C2
MDL No. :	MFCD02234511
InChI Key :	NSWIROGSZPXREF-UHFFFAOYSA-N
Pubchem ID :	135685723

Safety of [ 1218-69-5 ]

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

Application In Synthesis of [ 1218-69-5 ]

* 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 [ 1218-69-5 ]

[ 1218-69-5 ] Synthesis Path-Downstream 1~35

1
[ 57508-48-2 ]
[ 1218-69-5 ]
[ 38370-06-8 ]

References: [1]Helvetica Chimica Acta,1972,vol. 55,p. 1566 - 1595.

2
[ 54610-69-4 ]
[ 1218-69-5 ]
[ 38358-86-0 ]

References: [1]Helvetica Chimica Acta,1972,vol. 55,p. 1566 - 1595.

3
[ 1218-69-5 ]
N-(2-Hydroxybenzoyl)-2-hydroxybenzamidin [ No CAS ]

References: [1]Helvetica Chimica Acta,1972,vol. 55,p. 1566 - 1595.

4
[ 65-45-2 ]
[ 69-72-7 ]
[ 1218-69-5 ]

Yield	Reaction Conditions	Operation in experiment
95%		Xvlene (150 mL) and salicylic acid (1) (100 g, 0,072 mol) were added to a 500 mL, 4 necked round-bottom flask equipped with a mechanical stirrer and thermocouple. Thion I chloride (87 g, 0.036 mol)) was added at 10C to 15C. After addition of thionyl chloride, the reaction mass was stiired at 10C to 15C for 30 minutes, The reaction mass was further heated at 35C-40C for 1 hr. A solution of salicylamide (2) (100 g, 0.072 mol) in 200 mL of xylene was added to the reaction mass at 25C to 30C. After addition, the reaction mass was gradually heated at 80C to 120C and stirred for 2 hrs, After completion of reaction, excess of xvlene was removed under vaccum. Methanol 200 mL was added to the reaction mass at 70C to 80C and stirred for 1 hour. The reaction mass was cooled gradually at 25C to 30C. The solid was filtered and washed with methanol and dried at 55C to 60C under vacuum tray drier to yield 165 g 2-(2-hvdroxyphenvI)-4- 1 ,3-benzoxazin-4-one (3). Yield 95%, rn.p. 239C. LCMS: m/z = 240.22 (M+H) calcd, for C14H9N30: 239.2.
76%	With pyridine; thionyl chloride; In 5,5-dimethyl-1,3-cyclohexadiene; at 20℃;Reflux;	Salicylic acid (6.04 g, 43.75 mmol), salicylamide (5.00 g, 36.46 mmol) and pyridine (0.37 mL, 4.63 mmol) were heated at reflux in xylene (18.00 mL) for 15 min. Thionyl chloride (5.83 mL, 80.21 mmol) was added with vigorous stirring over a period of 4 h, with further stirring for 16 h at room temperature. Xylene was removed by concentration in vacuo, and resulting solid residue was suspended in ethanol (15.00 mL) and acetic acid (0.36 mL). The mixture was heated to reflux and cooled to room temperature. The solid precipitate was isolated and dried to yield 2-(2-Hydroxyphenyl)-benzo-4H-[1,3]-oxazin-4-one (1) (6.59 g, 27.54 mmol, 76%) as yellow solid.
54%	With 1,3,5-trichloro-2,4,6-triazine; triethylamine; In toluene; at 80℃; for 16h;Dean-Stark; Inert atmosphere;	In a round bottom flask fitted a reflux condenser and a Dean-Stark trap, a suspension of salicylic acid (27.6 g, 0.2 mol), salicylamide (23.3 g, 0.17 mol) and 2,4,6-trichloro-1,3,5-triazine (24.8 g, 0.134 mol) in 600 mL toluene was heated under a nitrogen atmosphere for 30 minutes at 80C. Then triethylamine (28.08 mL, 0.2 mol) was added slowly to the solution and the resulting mixture was heat to reflux for 16 h. Precipitation of some solid began to occur during the reaction; the reaction mixture was cooled to about 80C and then filtered hot (by suction) as quickly as possible to remove the solid mixture of triethylamine hydrochloride, cyanuric acid and other solids. The filtrate was then evaporated and the resulting crude solid was recrystallized39 from ethanol (600 mL) to give21.9 g (54% yield) of benzoxazinone 4 in better than 98% purity as a very pale yellow solid. All spectroscopic data of product 4 matched those of an authentic sample.

43%	With pyridine; thionyl chloride; In N,N-dimethyl-formamide; for 4h;Reflux;	Salicylic acid (II) (2g, 14.5mmol), salicylamide (III) (1.53g, 11.1mmol) and N, N-dimethylformamide (1ml) were added to the solvent xylene (20ml), heated Reflux and mix well.After adding thionyl chloride (1.9 g, 16.0 mmol), it was stirred well for 4 h.A large amount of HCl and SO2 gas are generated during the reaction, and a tail gas absorption device is used. After a period of reaction, crystals were precipitated and stirring was continued for 30 min. After completion of the reaction, the mixture was distilled under reduced pressure, and the solvent was evaporated. The solid was washed with a mixed solution of ethanol (30 ml) and acetic acid (1 ml) and recrystallized from 2-methoxyethanol.The yellow-green solid product IV (1.14 g, 4.78 mmol, 43%) was obtained.
39.3%		Example 1 Preparation of 2-(2-hydroxyphe41)-benz[1,3]oxazin-4-one A mixture of dichloromethane (200 ml), salicylic acid (50.0 gm) and p-toulenesulfonyl chloride (69 gm) were cooled to 10-15 C. Diisopropyl ethyl-amine (139.0 ml) was added drop-wise to the above mixture at 10-20 C. Reaction mass was stirred for 10 min at 10-20 C. and raised the temperature to 25-30 C. The reaction was maintained for 2 hours at 25-30 C. Reaction mass was cooled 0-5 C. Purified water (200 ml) was charged to the above mixture and stirred for 15 minutes. The layers were separated. Salicylamide (39.6 gm) and toluene (200.0ml) were heated to 85-90 C. and the above organic layer was added drop-wise into salicyliamide solution with simultaneous distillation of solvent at 85-90 C. and distilled the solvent upto the reaction mass temperature reaches to 110-120 C. and further reaction was maintained for 3hrs at 110-120 C. Further solvent was distilled under atmospheric pressure upto reaction mass temperature reaches to 140-160 c and further the reaction was maintained for 1-2 hrs at 140-160 C. until the starting material disappears. Reaction mass was cooled to 75-80 C. and distilled off completely toluene under vacuum. Ethanol (50 ml) was added to the above reaction mass at 75-80 C. Reaction was stirred for 15 min and distilled off the ethanol at 75-80 C. Further ethanol (50.0 ml) was added stir for 5-10 min. Ethanol was distilled off completely under vacuum at 75-80 C. Ethanol (150 ml) was charged into above contents at 75-80 C. The contents were maintained for 1 hour at 75-80 C. and slowly cooled to 0-5 C. Reaction mass was maintained for 2 hrs at 0-5 C. The reaction mass was filtered and washed with ethanol (50.0 ml). Dried the compound at 50-55 C. Yield: 39.30%.
39%	With pyridine; thionyl chloride; In 5,5-dimethyl-1,3-cyclohexadiene; ethanol; for 4h;Reflux;	Salicylic acid (2 g, 14.5 mmol), salicylamide (1.53 g, 11.1 mmol)and pyridine (1 ml) were refluxed in xylene (20 mL). Thionylchloride (1.9 g, 16.0 mmol) was added with vigorous stirring over aperiod of 4 h. An intense evolution of SO2 and HCl was noted. At theend of the reaction, the product started to crystallize. Stirring wascontinued for an additional 30 min, and the xylenewas removed byreduced-pressure distillation. The resulting solid residue was suspendedin EtOH (30 mL) and acetic acid (1 mL). The mixture washeated gently and then allowed to cool to 20 C. The precipitatewasfiltered and recrystallized from 2-methoxyethanol (35 mL). Yield:yellow-green solid (1.04 g, 4.34 mmol, 39%). m.p. 202.2e204.6 C.1H NMR (500 MHz, DMSO-d6) d12.95 (s, 1H), 8.25e8.21 (m, 1H),8.08 (dd, J1 7.8, J2 1.5 Hz, 1H), 7.98e7.94 (m, 1H), 7.81 (dd,J1 8.4, J2 0.6 Hz, 1H), 7.68e7.60 (m, 2H), 7.13e7.08 (m, 2H). ESIMS:m/z. Calculated for C14H9NO3 239.06; found[MH] 240.0655.
	With pyridine; thionyl chloride; In xylene; for 11h;Reflux;Product distribution / selectivity;	Mixture of salicylic acid (100 grams), salicylamide (89.3 grams), pyridine (15.2 ml) and xylene (600 ml) was heated to reflux temperature. Thionyl chloride (100.5 ml) was added to the above mixture at reflux temperature for 3 hours. Intense evolution of SO2 and hydrochloric acid was observed, the reaction mixture was then stirred for 8 hrs. Xylene was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was suspended in methanol (200 ml) and raised the temperature to 60-65C. The reaction mixture was stirred for one hour at 60-65C and cooled to 0-5C and further stirred' for one hour. The solid obtained was filtered, washed with methanol and dried to get the title compound.Yield: 130 grams
		Example 1; Preparation of 2-(2-Hydroxyphenyl)-4H-1,3-benzoxazine-4-oneSalicylic acid (50 gm) was taken in xylene (250 ml) followed by the addition of thionyl chloride (64.5 gm) drop wise to the reaction mixture at 25-30 C. The reaction mixture was stirred for 90 minutes at 40-45 C. The excess thionyl chloride was removed by distillation. Salicylamide (49.7 gm) was added to the resulting mixture and followed by the distillation of xylene up to a reaction temperature of 170 C. The reaction mixture was further stirred for 60 minutes at 80 C. followed by the addition of ethanol (80 ml) and refluxed for 15 minutes. The resulting mass was cooled to 25 C. and stirred for 30 minutes at the same temperature. The resulting solid was filtered and dried to produce 43 gm of 2-(2-hydroxyphenyl)-4H-1,3-benzoxazine-4-one as slightly yellow crystals. (Melting point: 206-208 C.).
		Example-I [68] Preparation of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one [69] [70] Xylene (1.5 L) and salicylic acid (1 Kg.) was added to a 5 L 4-neck round bottom flask equipped with a mechanical stirrer and thermocouple. Thionyl chloride (1.29 kg) was added at 10 oC to 15oC. After addition of thionyl chloride reaction mass is stirred at 10 0C to 15oC for 30 minutes. Reaction mass is heated at 35-40 0C for 1 hr. Salicylamide solution (0.891 kg in 2.0 lit of Xylene) was added in reaction mass at 25 0 C -30 0 C. After addition reaction mass was gradually heated at 80 0C - 126 0C and stirred for 2 hrs. After the completion of reaction excess of Xylene was distilled out. Methanol was added in the reaction mass at 70 0C -80 0C and stirred for 1 hr. gradually cooled the reaction mass at 25-30 0C. Filtered the solid and washed with Methanol and sucked it dry. Dry the obtained solid at 55-60 0C under vacuum tray drier.
		EXAMPLE-I Preparation of 2-(2-Hydroxyphenyl) Benz [e] [1, 3] Oxazin-4-One Xylene (1.5 L) and salicylic acid (1 Kg.) was added to a 5 L 4-neck round bottom flask equipped with a mechanical stirrer and thermocouple. Thionyl chloride (1.29 kg) was added at 10 C. to 15 C. After addition of thionyl chloride reaction mass is stirred at 10 C. to 15 C. for 30 minutes. Reaction mass is heated at 35-40 C. for 1 hr. Salicylamide solution (0.891 kg in 2.0 lit of Xylene) was added in reaction mass at 25 C.-30 C. After addition reaction mass was gradually heated at 80 C.-126 C. and stirred for 2 hrs. After the completion of reaction excess of Xylene was distilled out. Methanol was added in the reaction mass at 70 C. -80 C. and stirred for 1 hr. gradually cooled the reaction mass at 25-30 C. Filtered the solid and washed with Methanol and sucked it dry. Dry the obtained solid at 55-60 C. under vacuum tray drier.
	With pyridine; thionyl chloride; In 5,5-dimethyl-1,3-cyclohexadiene;Reflux;	Salicylic acid (b) 24.9 g was sequentially added to a 250 mL three-necked flask. Salicylamide (c) 20.6g, 1.5 mL of pyridine and 30 mL of xylene, Slowly add 23.7 mL of thionyl chloride under stirring. After heating and refluxing, The solvent was removed under reduced pressure. The residue is dissolved by heating with a mixed solvent of ethanol and acetic acid. cool down, filter, Ethylene glycol monomethyl ether recrystallized, Yellow needle crystals, Mp 226-227 C.
15 g	With pyridine; aluminum (III) chloride; thionyl chloride; In o-xylene; at 25 - 125℃; for 1.5h;	10 grams of salicylamide, 10.90 grams of salicylic acid, 0.20 grams aluminum chloride and 1.17 grams pyridine were added to 55 ml o-xylene at 25-30C. Reaction mass temperature was raised to 115-125C and then 16.70 grams thionyl chloride was slowly added over a period of 60 min at 1 15-125C and maintained at 1 15-125C for 30 min. The reaction mass was cooled to 25-30C and further added 33 ml absolute alcohol. The obtained slurry product was filtered and washed with absolute alcohol to give 15 grams of pale yellow crystalline 2-(2- hydroxyphenyl)-4H- l,3-benzoxazin-4-one having chromatographic purity about (0077) 95.5 %. (0078) The above product was purified by refluxing in absolute alcohol in presence of sodium methoxide followed by glacial acetic acid addition and then cooled to room temperature. The product was filtered and washed with absolute alcohol to obtain pure 2- (2-hydroxyphenyl) -4H- 1 , 3 -b enzoxazin-4-one having chromatographic purity about 99.5 %.
	With pyridine; thionyl chloride; In 5,5-dimethyl-1,3-cyclohexadiene; at 130 - 140℃; for 2h;	General procedure: Substituted benzoic acid (1.2e2.0 g, 10 mmol) and o-hydroxybenzamide (1.5e2.3 g, 11 mmol) were added into 20 mL of xylene,then anhydrous pyridine (catalytic amount) was added, and thionylchloride (1.5 mL, 20 mmol) in xylene (8 mL) was added dropwiseover 30 mins at room temperature. After that, stirring was undertakenat 130e140 C. The mixturewas stirred for 2 h (TLC show acidwas consumed) and the solvent was distilled off under reducedpressure to obtain intermediate. The intermediate, 4-hydrazinobenzene-1-sulfonamide hydrochloride (1.1 g, 5 mmol)and triethylamine (1.0 g,10 mmol), were added to 15 mL of absoluteethanol, and the mixture was stirred at 80 C for 18 h. When thereaction was complete, the solution was filtered, and saturatedsodium bicarbonate was added to adjust pH to 7. The solution wasextracted with ethyl acetate, and the organic layer was washedwith 20 mL of saturated brine and dried over anhydrous sodium.The solvent was evaporated under reduced pressure to obtain thetarget compounds. The target compounds were recrystallized frommethanol.

References: [1]Journal of labelled compounds and radiopharmaceuticals,2015,vol. 58,p. 163 - 165.
[2]Patent: WO2016/203488,2016,A1 .Location in patent: Page/Page column 8.
[3]Patent: US2016/296629,2016,A1 .Location in patent: Paragraph 0060-0062.
[4]Asian Journal of Chemistry,2015,vol. 27,p. 1959 - 1960.
[5]European Journal of Inorganic Chemistry,2004,p. 4177 - 4192.
[6]Organic Preparations and Procedures International,2015,vol. 47,p. 483 - 489.
[7]Patent: CN106554770,2018,B .Location in patent: Paragraph 0008; 0021; 0032; 0033; 0035; 0036.
[8]Patent: US2013/338356,2013,A1 .Location in patent: Paragraph 0020.
[9]Journal of Molecular Structure,2016,vol. 1111,p. 1 - 8.
[10]Helvetica Chimica Acta,1972,vol. 55,p. 1566 - 1595.
[11]Patent: WO2011/21218,2011,A2 .Location in patent: Page/Page column 20.
[12]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 9.
[13]Patent: WO2012/69946,2012,A1 .Location in patent: Page/Page column 4-5.
[14]Synthetic Communications,2012,vol. 42,p. 3200 - 3210.
[15]Patent: US2014/39199,2014,A1 .Location in patent: Paragraph 0043.
[16]Patent: CN108727287,2018,A .Location in patent: Paragraph 0023; 0025.
[17]Patent: WO2019/16637,2019,A1 .Location in patent: Page/Page column 12.
[18]European Journal of Medicinal Chemistry,2020,vol. 190.

5
[ 65-45-2 ]
[ 1441-87-8 ]
[ 1218-69-5 ]

Yield	Reaction Conditions	Operation in experiment
~ 66%		The solution obtained in example 1 is poured into a second reactor, maintained at a temperature of 1 10 C and containing 7 kg of salicylamide and 1 1 kg of toluene. The resultant mass is allowed to react under reflux at approximately 1 15 C, for 20 hours, continually removing the water liberated by the reaction. The solution is then cooled to 65 C, and 5 kg of methanol is added. Distillation is performed until a dense residue is obtained, to which 25 kg of denatured ethanol (denatured using cyclohexane-methanol) is then added; the whole is heated under reflux for 30 minutes, then cooled to ambient temperature and centrifuged, finally, it is washed with 7 kg of denatured ethanol.Approximately 8 kg of compound (II), dry equivalent, is obtained, determined by a weight loss test on step of the product, for a yield equal to approximately 66% in this step. The product is analysed by HPLC, determining a purity of more than 99.0%.
		a 2-(2-Hydroxyphenyl)benz[e][1,3]oxazin-4-one 106.0 g of salicyloyl chloride and 93.0 g of salicylamide are mixed and heated at 170 C. for 30 min until hydrogen chloride no longer escapes. The mixture is cooled and the residue is crystallized from ethanol. After drying, 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one is obtained as slightly yellow crystals of m.p. 206-208 C.
	In o-xylene; at 130 - 160℃;Product distribution / selectivity;	0.255 moles of Salicylamide was dissolved in 70 ml of O-xylene and the temperature was raised to 130-1600C. Xylene solution of Salicyloyl chloride (prepared in example- 1) was added to the resulting solution over a period of 90-120 minutes at the same temperature and maintained for 3-5 hours till salicylamide disappears. After reaction is over, the reaction mass was maintained for 2-3 hours at 130-1600C. Subsequently, xylene was distilled out completely at atmospheric pressure. To the resultant compound 35 ml of ethanol was added, distilled off under vacuum and fresh ethanol was again added. The reaction temperature was raised to 75-800C and maintained for 60 minutes followed by cooling of the reaction mass to 0- 50C and maintained for 60 minutes. The resultant mixture was then filtered, washed with 35 ml ethanol and dried under vacuum at 450C for 4-6 hours to produce 52 gm of 2-(2-Hydroxy phenyl) benz[e] [1, 3] oxazin-4-one.

References: [1]Patent: WO2012/131017,2012,A1 .Location in patent: Page/Page column 7.
[2]Helvetica Chimica Acta,1972,vol. 55,p. 1566 - 1595.
[3]Patent: US6465504,2002,B1 .
[4]Patent: WO2010/23685,2010,A2 .Location in patent: Page/Page column 6; 8.
[5]Angewandte Chemie - International Edition,2019,vol. 58,p. 8773 - 8778.
Angew. Chem.,2019,vol. 131,p. 8865 - 8870,6.

6
[ 108-24-7 ]
[ 1218-69-5 ]
[ 86245-85-4 ]

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.

7
[ 108-24-7 ]
[ 1218-69-5 ]
[ 86245-84-3 ]

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.

8
[ 141-43-5 ]
[ 1218-69-5 ]
[ 20237-92-7 ]
[ 79576-69-5 ]

References: [1]Zeitschrift fur Chemie,1981,vol. 21,p. 261.

9
[ 141-43-5 ]
[ 1218-69-5 ]
[ 24201-18-1 ]
[ 79576-69-5 ]

References: [1]Zeitschrift fur Chemie,1981,vol. 21,p. 261.

10
[ 141-43-5 ]
[ 63963-47-3 ]
[ 20237-92-7 ]
[ 1218-69-5 ]
[ 79576-69-5 ]
[ 65-45-2 ]

References: [1]Zeitschrift fur Chemie,1981,vol. 21,p. 261.

11
[ 113-00-8 ]
[ 1218-69-5 ]
[ 19190-02-4 ]

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.

12
[ 546-82-7 ]
[ 1218-69-5 ]
[ 86245-89-8 ]

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.

13
[ 1218-69-5 ]
[ 107-15-3 ]
[ 1565-39-5 ]
[ 65-45-2 ]

References: [1]Zeitschrift fur Chemie,1981,vol. 21,p. 261.
[2]Zeitschrift fur Chemie,1981,vol. 21,p. 261.

14
[ 1218-69-5 ]
[ 100-63-0 ]
[ 86245-87-6 ]

Yield	Reaction Conditions	Operation in experiment
	With propionic acid; at 132℃; for 2h;	General procedure: A suspension of (0.04 mol) 2-(2-hydroxyphenyl) benz[l,3]oxazin-4-one (3), (0.0524 mol) 4-substituted phenyl hydrazines (5a-d) and 57.0 mL of n-propionic acid was heated to boiling temperature of the reaction mixture and kept at this temperature (132C) for 2 hours, After completion of the reaction. 57 mL of ethyl acetate was added to the suspension after cooling and the suspension was further stirred for 30 minutes. The resulting crystalline product was filtered, washed with 30 ml of ethyl acetate on the filter and dried to a constant weight. A white crystalline product obtained was N-substituted 3,5- bis(2-hydroxvphenyl)- 1 H-i ,2,4-triazol- 1 -yl (6a-d). 4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yllbenzene (6a) : IR, v. cm?:3332.4 (C=N str.). 3066.3 (0-H, aromatic), 2930.3 (C-H str.), 2594.9 (N=N str.), 1660, 1609, 1591 (C=C, aromatic), 1557.2,1497 (triazinc ring str,), 835- 827 (C-C aromatic str.); ?H NMR (CDCI3), ppm : 6.90-7.09 (m, 4H, Ar-H).?37.37-7.49 (m, 8H, Ar-H), 8.04-8.06 (dd, IH, Ar-H), 10.08 (br. s, 2 -OH); C NMR ((CDCI3), ppm : 113.41 (ArC), 113.77 (ArC). 116.20 (ArC), 116.99(ArC), 119.16 (ArC), 119.63 (ArC), 123.82 (ArC), 126.98 (ArC), 128.85 (ArC),129.22 (ArC), 130.97 (ArC), 131.55 (ArC), 131.48 (ArC), 137.51 (ArC-N),151.46 (C=N), 155.63 (ArC-OH), 156.33 (CN), 158.62 (ArC-OH); LCMStn/z = 330.1 (M+1); calcd, for C23H27C1N40 : 329.5; Anal, Caic. forC23H27C1N40 : C, 72,94; H, 4.59; N, 12.76. Found : C, 72.80; H, 4.34; N. 12.73.
	With acetic acid; In ethanol; at 82℃;	Add in 150mL three-necked flasks 20mL absolute ethanol, 1 mL of phenylhydrazine(d), 0.5g key intermediate a, And 0.5 mL of acetic acid was added as a catalyst. Heating and refluxing for 2 h, After the reaction is over, The solvent was removed under reduced pressure. The residue was purified by column chromatography to give a white solid. The temperature of 150-151 C.

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.
[2]Patent: WO2016/203488,2016,A1 .Location in patent: Page/Page column 9.
[3]Patent: CN108727287,2018,A .Location in patent: Paragraph 0023; 0029-0031.

15
[ 1218-69-5 ]
[ 74619-49-1 ]

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.

16
[ 1218-69-5 ]
[ 74619-50-4 ]

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.
[2]Chemistry and biodiversity,2020.

17
[ 1218-69-5 ]
[ 74619-50-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; at 118 - 120℃; for 2h;	Add in a 100 mL three-necked flask 0.5g key intermediate a, 20mL hydrazine hydrate, Heating and refluxing for 2 h, After the reaction is over, Adding an appropriate amount of water to the reaction solution, a white solid precipitated, filter, Recrystallized from ethanol, A powdery solid was obtained with a melting point of 309-310 C.

References: [1]Zeitschrift fur Chemie,1981,vol. 21,p. 261.
[2]Patent: CN108727287,2018,A .Location in patent: Paragraph 0023; 0026-0028.

19
[ 619-67-0 ]
[ 1218-69-5 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In ethanol; for 2h;Reflux;	4-hydrazino-benzoic acid (1.40 g, 9.19 mmol), and triethylamine (1.28 mL, 9.19 mmol) were added to ethanol (40.00 mL) and refluxed for 15 min until all components have dissolved. To the clear solution was added (1) (1.40 g, 9.19 mmol) which was further refluxed for 2 h. After cooling to room temperature, water (5.00 mL) was added until perturbation was observed. The mixture was concentrated to 50% of total volume under reduced pressure, and aqueous 6 M HCl (31.00 mL) was added. The resulting precipitate was isolated and dried to yield 4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox) (2) (3.12 g, 8.36 mmol, 99%) as dark yellow solid.
93%	With propionic acid; In chlorobenzene; at 130℃; for 1h;Heating / reflux;Product distribution / selectivity;	A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of propionic acid <n="14"/>and 5 ml of chlorobenzene is heated to 130 0C. The mixture is maintained and stirred at this reflux temperature for 1 hour. After completion of the reaction, the mixture is cooled and poured onto crushed ice.The mixture is alkalized with sodium hydroxide until pH = 11 and extracted with 20 ml of ethyl acetate. After separation of the layers, the aqueous phase is filtered with active carbon and acidified with concentrated hydrochloric acid until pH = 1 to 2. The resulting suspension is stirred for 10 minutes and then it is filtered and the crystals are washed with water. After drying, 1.01 g of precipitated deferasirox is obtained, i.e. 93% of the theory, with an HPLC content of 95.41% and a melting temperature of 253 to 262 0C.
91%	With propionic acid; In 1-methyl-pyrrolidin-2-one; at 120℃; for 1h;Product distribution / selectivity;	A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of N- methylpyrrolidone and 5 ml of propionic acid is heated to 120 0C. The mixture is maintained at this temperature and stirred for 1 hour. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.99 g of raw deferasirox is <n="13"/>obtained, i.e. 91 % of the theory, with an HPLC content of 92.9% and a melting temperature of 250 to 261 0C.

87%	With propionic acid; at 132℃; for 2h;Heating / reflux;Product distribution / selectivity;	A suspension of 10.65 g (44.5 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one, 7.97 g (52.4 mmol) of 4-hydrazinobenzoic acid and 57.0 ml of propionic acid is heated to the boiling temperature of the reaction mixture and is kept at this temperature (132 0C) for 2 hours. After completion of the reaction, 57 ml of ethyl acetate is added to the suspension after cooling and the suspension is stirred for 30 minutes.The resulting crystalline product is filtered, washed with 30 ml of ethyl acetate on the filter and dried to a constant weight. A white crystalline product weighing 14.38 g is obtained, i.e. 87% of the theory, with HPLC purity above 99.4% and a melting temperature of 260 to 265 0C.Precipitation of the raw product is performed in such a way that the raw product is dissolved in a sodium hydroxide solution (6.16 g in 60 ml of water) and extraction with 50 ml of ethyl acetate is carried out. After separation the aqueous layer is filtered with 0.5 g of active carbon and after filtration the solution is acidified with hydrochloric acid to pH = 1 to 2 and the resulting suspension is stirred at the temperature of 20 0C for 30 minutes. The precipitated product is aspirated and washed with water until neutral pH. After drying to a constant weight, 14.3 g are obtained, i.e. 86% of the theory, with an HPLC purity above 99.8% and melting temperature of 263 to 265 0C.The precipitated product is stirred up with ethyl acetate by stirring in a suspension with 57 ml of ethyl acetate at a temperature of 20 0C for 30 minutes. The stirred-up product is aspirated and washed with ethyl acetate. After drying to a constant weight, 13.56 g are obtained, i.e. 82% of the theory, with HPLC purity above 99.8%. Melting temperature: 264 to 266 0C.
87%	With propionic acid; In toluene; at 110℃; for 2h;Heating / reflux;Product distribution / selectivity;	A suspension of 0.7 g (2.93 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-liydrazinobenzoic acid in 8.0 ml of toluene and 5 ml of propionic acid is heated to its boiling point and is maintained at this temperature (110 0C) for 2 hours. After completion of the reaction, the reaction mixture is cooled and filtration is carried out. The crystalline product is washed with toluene and dried until dry.0.95 g of white product is obtained (87% of the theory), which contains 97.1% of deferasirox having a melting temperature of 256 to 263 0C.Precipitation of the raw product is performed in such a way that raw deferasirox is dissolved in a solution of 0.6 g of sodium hydroxide in 30.0 ml of water and the solution is extracted with ethyl acetate (1 x 30.0 ml). The aqueous phase is filtered with active carbon and the filtrate is acidified with concentrated hydrochloric acid until pH = 1 to 2. The suspension is stirred at the temperature of 20 0C for 1 hour and the precipitated product is filtered and washed with water. After drying, 0.73 g of precipitated deferasirox (67% of the theory) is obtained with a purity of 98.5 % and a melting temperature of 260 to 264 0C.
86%	In ethanol; for 3h;Reflux;	A solution of compound 4 (2.39 g, 10 mmol) and 4-hydrazinobenzoic acid (1.67g,11 mmol) was heated with stirring in 30 mL ethanol for 3 h at reflux. The reaction mixture was then cooled to room temperature; the precipitated solid was collected and dried under vacuum overnight. Recrystallization and decolorization with activated charcoal in ethanol afforded 3.21 g (86% yield) of deferasirox (6) as a white solid. All spectroscopic data of product 6 matched those of an authentic sample.
84%	With propionic acid; In ethyl acetate; at 92℃; for 2h;Heating / reflux;Product distribution / selectivity;	A suspension of 0.7 g (2.92 mmol) of 2-(24iydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 8 ml ethyl acetate and 5.0 ml of propionic acid is heated to its boiling point and maintained at this temperature (92 0C) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with ethyl acetate. After drying, 0.92 g of raw deferasirox is obtained, i.e. 84% of the theory, with an HPLC purity of 99.7% and a melting temperature of 258 to 263 0C.
82.5%	In ethanol;Heating / reflux;Product distribution / selectivity;	2-(2-hydroxyphenyl)benz(e)[l,3]oxazin-4-one (15.0 g) and 4-hydrazino- benzoic acid (10.5 g) are boiled under reflux in ethanol (225 ml). The reaction is checked for completion after 2 hours by Thin Layer Chromatography (TLC). If the reaction is not complete, the reaction mixture is stirred for an additional hour and the conversion is checked again until it is complete. If the reaction is complete, the mixture is cooled to room temperature and the precipitated solid material is filtered off, washed with ethanol and dried in vacuum. Yield: 82.5 %.
81%	With propionic acid; In N,N-dimethyl-formamide; at 150℃; for 1.5h;Product distribution / selectivity;	A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of N5N- dimethylformamide and 5 ml of propionic acid is heated up to 150 0C. The mixture is maintained at this temperature and stirred for 1.5 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.88 g of raw deferasirox is obtained, i.e. 81% of the theory, with an HPLC purity of 93% and a melting temperature of 255 to 262 0C.
80%	With triethylamine; In ethanol; for 2h;Reflux;	2-(2-Hydroxyphenyl)-4H-3,1-benzoxazin-4-one was prepared according to the previous reported procedure with a little modifications (Lattmann and Acklin, 1997; Ryabukhin et al., 1983). 4-Hydrazino-benzoic acid (11.5mmol, 1.75g) and Et3N (11.5mmol, 1.16g) were dissolved in boiling EtOH (80ml). Then, 2-(2-Hydroxyphenyl)-4H-1,3-benzoxazin-4-one (10.45mmol, 2.50g) was added to the clear solution, and the reaction mixture was refluxed for an additional 2h. After the completion of the reaction, the solution was cooled to room temperature, and water was added until the first sign of precipitation was observed. The mixture was concentrated to a total volume of 50% under reduced pressure and aqueous 6M HCl (40ml) was added. The resulting solid was filtered, washed with water and dried for 24h in vacuo (3.11g, Yield =80%). (0011) IR (KBr, cm-1) nu 33,317, 2540, 1680 (nuC=O), 1607, 1517, 1495, 1431, 1351, 1221, 988, 752. 1H NMR (CD3COCD3, ppm): delta=7.00 (s, 1H), 7.01-7.04 (m, 3H), 7.39 (m, 2H), 7.48 (d, 1H), 7.53 (d, 2H), 8.15 (d, 2H), 8.19 (d, 1H) 10.00 (s, OH), 10.78 (s, OH) ppm. 13C NMR (CD3COCD3, ppm) delta=113.7, 113.9, 116.6 (CH), 117.0 (CH), 119.5 (CH), 119.8 (CH), 124.0 (2 CH), 126.9 (CH), 130.4 (2 CH), 130.5, 130.7 (CH), 131.4 (CH), 132.6, 141.9 (CH), 152.1, 155.6, 156.4, 160.4, 165.7 (C=O) ppm. MS (m/z) for C21H15N3O4=(374) Anal. Calc. for C21H15N3O4: C 67.56, H 4.05, N 11.25; found C 67.16, H 4.09, N 10.86.
79%	With methanol; In dichloromethane; at 0 - 70℃; for 7h;	Example 2: Preparation of Deferasirox[0018] A mixture of methanol (450.0 ml), 2-(2-hydroxyphenyl)-benz[l ,3]oxazin- 4-one (30.0gm) were stir for 10 min at 25- 30C. To the above contents 4- hydrazino benzoic acid (20.03gm) was added. The contents were heated to reflux temperature 65-70C. The contents were maintained for 4 hours at 65-70C. The reaction mass was cooled slowly to 0-5C and maintained it for 1 hour at 0-5C. The reaction mass was filtered and washed with methanol (30.0 ml). Compound was taken into methylene chloride and stir for 10 min 25 -30C. The contents were heated to reflux temperature (40-45C) and maintained the contents for 1 hr at reflux temperature. Cool the contents to .25- 30C and stirred for lhr at 25 - 30C. The reaction mass was filtered and washed with methylene chloride (30.0ml). Dried the compound at 60-65C. Yield: 79.0%.
~ 77%		The moist product obtained at the end of example 2 is placed in a reactor, together with 4.88 kg of 4-hydrazinobenzoic acid and 48 kg of a 3 wt.% toluene/ethanol mixture. The mass is heated under reflux (approximately 77 C) for 2 hours. To the mass maintained with heating under reflux, 12 kg of DMF is then added, and heating under reflux is continued (at a temperature of approximately 80 C) until complete dissolution of the components present in the mixture is observed. 400 g of pharmaceutical quality decolourising carbon is then added. The suspension is heated under reflux (approximately 80 C) with stirring for 30 minutes, then it is cooled to 60 C and filtered. The filtered solution is placed in a reactor, heated under reflux, and 800 g of 85 wt.% of phosphoric acid, and 24 kg of distilled water are added. A precipitate is formed, which is heated under reflux (approximately 80 C) with continuous stirring for 30 minutes, after which the mixture is cooled to 30 C, centrifuged, and the solid is washed with a mixture consisting of 24 kg of distilled water and 8 kg of 3% toluene/ethanol.9.6 kg of raw deferasirox, dry equivalent, is obtained, determined by a weight loss test on step of the product, for a yield equal to approximately 77% in this step. The product is analysed by HPLC, determining a purity of more than 99.8%. By HPLC analysis it is determined that the 4-hydrazinobenzoic acid content of the product is below 0.5 ppm (which represents the limit of detection, LOD, of the analytical method .).
60%	With methoxypropionic acid; at 100℃; for 1h;Product distribution / selectivity;	A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of methoxypropionic acid is heated to 100 0C. The mixture is maintained and stirred at this temperature for 1 hour. After completion of the reaction, the mixture is cooled and 5 ml of ethyl acetate are added. The resulting mixture is stirred for 10 minutes, then it is filtered and the crystals are washed with ethyl acetate. After drying, 0.66 g of raw deferasirox is obtained, i.e. 60% of the theory, with an HPLC content of 99.3% and a melting temperature of 259 to 263 0C.
55%	With trichloroacetic acid; In toluene; at 110℃; for 3h;Product distribution / selectivity;	A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 g of trichloroacetic acid and 5 ml of toluene is heated to 110 0C. The mixture is maintained and stirred at this temperature for 3 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water and ethyl acetate. After drying, 0.6 g of raw deferasirox is obtained, i.e. 55% of the theory, with an HPLC content of 99.56% and a melting temperature of 258 to 262 0C.
50%	With propionic acid; In 2-methyltetrahydrofuran; at 98℃; for 2h;Heating / reflux;Product distribution / selectivity;	A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 8 ml of 2- methyltetrahydrofuran and 5.0 ml of propionic acid is heated to its boiling point and maintained at this temperature (98 0C) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with 2-methyltetrahydrofuran. After drying, 0.55 g of raw deferasirox is obtained, i.e. <n="11"/>50% of the theory, with an HPLC purity of 95.3% and a melting temperature of 255 to 262 0C.
49%	With LACTIC ACID; at 115℃; for 2h;Heating / reflux;Product distribution / selectivity;	A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of lactic acid is heated to its boiling point and maintained at this temperature (115 0C) for 2 hours. After completion of the reaction the mixture is cooled down, causing separation of the crystalline product. 5 ml of ethyl acetate are added. After drying, 0.53 g of raw deferasirox is obtained, i.e. 49% of the theory, with an HPLC content of 94% and a melting temperature of 248 to 260 0C.Precipitation of the raw product is performed in such a way that raw deferasirox is dissolved in a solution of 0.23 g of sodium hydroxide in 20.0 ml of water and the solution is extracted with ethyl acetate (1 x 20.0 ml). The aqueous phase is filtered with active carbon and the filtrate is acidified with 0.75 ml of concentrated hydrochloric acid until pH = 1 to 2. The suspension is stirred at a temperature of 20 0C for 1 hour and the precipitated product is filtered and washed with water. After <n="12"/>drying, 0.31 g of precipitated deferasirox is obtained, i.e. 29% of the theory, with a purity of 98.5% and a melting temperature of 261 to 2640C.The precipitated product is stirred up in ethyl acetate by stirring in a suspension with 10 ml of ethyl acetate at a temperature of 20 0C for 30 minutes. The stirred-up product is aspirated and washed with ethyl acetate. After drying to a constant weight, 0.19 g is obtained, i.e. 17% of the theory, with a purity above 99.0%. Melting temperature: 258 to 263 0C.
	In ethanol;	EXAMPLE 5 4-[3,5-Bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid 5.0 g of <strong>[1218-69-5]2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one</strong> and 3.5 g of 4-hydrazinobenzoic acid are boiled under reflux for 2 h in 75 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid remains as colorless crystals of m.p. 264-265 C.
	In methanol; for 2h;Reflux;	2-(2-Hydroxyphenyl)-4H-l,3-benzoxazin-4-one (25g, 0.1045 mol), 4-hydrazinobenzoic acid (17.5 g, 0.115 mol) and methanol (375 ml) were added to a round bottom flask. The reaction mixture was heated to reflux temperature and refluxed for 2 hours. The resulting mass was cooled to 25C and then filtered to isolate the solid product. The wet material was added to methanol (1625 ml) and heated to 65 to 660C to provide a clear solution. The resulting solution mass was cooled to 25C, and the separated solid was filtered and then dried to produce 28.5 g of crude deferasirox (etaPLC Purity: 99.8%, content of 4-hydrazinobenzoic acid impurity: 60 ppm).
		0.1945 moles of 2-(2-Hydroxy phenyl) benz[e] [1, 3] oxazin-4-one was dissolved in 750 ml of methanol and 0.2305 moles of 4-Hydrazino benzoic acid was added at 25-300C. Subsequently, the temperature of the reaction mixture was raised to 65-700C and maintained for 3-4 hours at the same temperature. The reaction mass was cooled to 25-300C followed by 0-50C and maintained for 60 minutes. The reaction mass was then filtered and washed with chilled 100 ml of methanol.175 ml of dimethyl formamide was added to the resultant solid and stirred for 15-20 minutes to get a clear solution. The above DMF solution was slowly added to a mixture of 700 ml D M water and 14 ml concentrated HCl in 60 minutes at 25-35C and maintained for 60-90 minutes at the same temperature. The mixture was the filtered and washed with water (4 X 140 ml), dried under vacuum at 50-600C for 4-6 hours to produce 70 gm of crude 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l- yl) benzoic acid.The resultant solid obtained from methanol was suspended in water and heated to 50-100 C, cooled and filtered to give 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid, free from sulfated ash.
	In methanol; at 60 - 65℃; for 5h;Product distribution / selectivity;	4-hydrazinobenzoic acid (38 grams) was added to the mixture of 2-(2-hydroxyphenyl)- benz[e][l,3]oxazin-4-one obtained as per example-3 and methanol (1 L) and heated to 60-65C then stirred for 5 hours at reflux temperature. The reaction mixture was cooled to 0-5 C stirred for 1.5 hours. The solid formed was filtered, washed with methanol and then dried to get the title compound.Yield: 75 grams; Purity by HPLC: 99.77 %; impurity at 2.1 RRT : 0.01%.Particle size distribution: D(0.1):2.40 mum; D(0.5):6.28 mum; D(0.9): 12.98 mum; D(1.00): 21.27 mum.
	In ethanol; for 2h;Reflux;	Example 3; Preparation of 4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (Deferasirox)2-(2-Hydroxyphenyl)-4H-1,3-benzoxazine-4-one (25 gm, 0.1045 moles) and 4-hydrazinobenzoic acid (17.5 gm, 0.115 moles) were taken in ethanol (375 ml). The reaction mass was heated to reflux and refluxed for 2 hours. The resulting mass was cooled to 25 C., the resulting solid was filtered and dried to produce 30.4 gm of 4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (Melting point: 264 C.).
	In methanol; for 2h;Reflux;	REFERENCE EXAMPLEPreparation of Deferasirox (Crude)2-(2-Hydroxyphenyl)-4H-1,3-benzoxazin-4-one (25 g, 0.1045 mol), 4-hydrazinobenzoic acid (17.5 g, 0.115 mol) and methanol (375 ml) were added to a round bottom flask. The reaction mixture was heated to reflux temperature and refluxed for 2 hours. The resulting mass was cooled to 25 C. and then filtered to isolate the solid product. The wet material was added to methanol (1625 ml) and heated to 65 to 66 C. to provide a clear solution. The resulting solution mass was cooled to 25 C., and the separated solid was filtered and then dried to produce 28.5 g of crude deferasirox (HPLC Purity: 99.8%, content of 4-hydrazinobenzoic acid impurity: 60 ppm).
	With potassium hydrogensulfate; In ethanol; water; at 25 - 75℃; for 2.75h;Industry scale;	Example- II [73] Preparation of Deferasirox [74] [75] 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one (1.0 kg) and 4-Hydrazino benzoic acid (0.699 kg), Ethanol (9.0 lit), Water (1.0 lit) was stirred at 25-350C in round bottom flask. Followed by addition of Potassium hydrogen sulphate (0.15 kg) into the reaction mass and heated the reaction mass at 70-75 0 C for two hrs. Cooled the reaction mass at 25-30 0C and stirred for 45 minutes. Filtered off the solid and washed with ethanol. Obtained solid and water (1.0 lit) stirred at 25-30 C for 15 minutes and then heated at 50- 55 0C. for 1 hr. The solid was filtered at 50-55 0C and washed with water. Charge this wet cake in DMF (5.0 lit) and stirred at 25-30 0C. In this solution 30% H2O2 was added at 25-30 0C within 1 hr. Followed by addition of water at 25-30 0C and stirred for 30 minutes. Filtered off the solid and washed it with water. The obtained solid was added in pre heated water and stirred at 45-50 0C. Gradually increased the temperature up to 65-75 0C & stir it for 60 min. cooled the reaction mass at 45-50 0C and stirred it for 40 minutes. The precipitated Deferasirox filtered off and washed with water. Dry the solid at 65-75 0C in vacuum tray drier.
		Example 2 Preparation of Deferasirox A mixture of methanol (450.0 ml), 2-(2-hydroxyphenyl)-benz[1,3]oxazin-4-one (30.0 gm) were stir for 10 min at 25-30 C. To the above contents 4-hydrazino benzoic acid (20.03 gm) was added. The contents were heated to reflux temperature 65-70 C. The contents were maintained for 4 hours at 65-70 C. The reaction mass was cooled Slowly to 0-5 C. and maintained it for 1 hour at 0-5 C. The reaction mass was filtered and washed with methanol (30.0 ml). Compound was taken into methylene chloride and stir for 10 min 25-30 C. The contents were heated to reflux temperature (40-45 C.) and maintained the contents for 1 hr at reflux temperature. Cool the contents to 25-30 C. and stirred for 1 hr at 25-30 C. The reaction mass was filtered and washed with methylene chloride (30.0 ml). Dried the compound at 60-65 C. Yield: 79.0%.
	With potassium hydrogensulfate; In ethanol; water; at 70 - 75℃; for 2h;	EXAMPLE-II Preparation of Deferasirox 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one (1.0 kg) and 4-Hydrazino benzoic acid (0.699 kg), Ethanol (9.0 lit), Water (1.0 lit) was stirred at 25-35 C. in round bottom flask. Followed by addition of Potassium hydrogen sulphate (0.15 kg) into the reaction mass and heated the reaction mass at 70-75 C. for two hrs. Cooled the reaction mass at 25-30 C. and stirred for 45 minutes. Filtered off the solid and washed with ethanol. Obtained solid and water (1.0 lit) stirred at 25-30C for 15 minutes and then heated at 50- 55 C. for 1 hr. The solid was filtered at 50-55 C. and washed with water. Charge this wet cake in DMF (5.0 lit) and stirred at 25-30 C. In this solution 30% H2O2 was added at 25-30 C. within 1 hr. Followed by addition of water at 25-30 C. and stirred for 30 minutes. Filtered off the solid and washed it with water. The obtained solid was added in pre heated water and stirred at 45-50 C. Gradually increased the temperature up to 65-75 C. & stir it for 60 min. cooled the reaction mass at 45-50 C. and stirred it for 40 minutes. The precipitated Deferasirox filtered off and washed with water. Dry the solid at 65-75 C. in vacuum tray drier.
	With triethylamine; In ethanol; at 82℃;	1.75 g of 4-hydrazinobenzoic acid(e) and 1.16 g of NEt3 were completely dissolved in 30 mL of hot ethanol solution. Add 2.50g of key intermediate a, The reaction was heated to reflux for 2-3 h. After the reaction is over, Concentrate to half volume under reduced pressure, Add the right amount of water, Adjust the pH to 5 with hydrochloric acid, There are white flocs, Filtered to purify a pale yellow solid. Melting point 261-262 C.
13 g	In ethanol; for 2h;Reflux;	10 grams of 2-(2-Hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (Deferasirox cyclic compound) and 6.5 grams of 4-hydrazinobenzoic acid were boiled under reflux temperature for 2 hours in 70 ml absolute alcohol. The product was precipitated during reflux and cooled to room temperature, filtered and washed with absolute alcohol (2x10 ml). The obtained wet Deferasirox (16grams) was dissolved in absolute alcohol (430 ml) at reflux temperature, charcolized, filtered through hyflo bed at hot condition and then washed with hot absolute alcohol (20 ml). Filtrate was distilled off until the mass volume reaches about 100 ml and cooled to room temperature. The precipitated product was filtered and washed with absolute alcohol. The product was dried at 50-55 C for 6 hours, obtained about 13 grams of pure 4-[3,5-Bis (2-hydroxyphenyl)- lH- l ,2,4-triazol-l-yl]benzoic acid [HPLC Purity: 99.95 %; 'hydrazino impurity' : l lO ppm].

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[ 98-71-5 ]
[ 1218-69-5 ]
4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzenesulfonic acid [ No CAS ]

References: [1]European Journal of Inorganic Chemistry,2004,p. 4177 - 4192.

21
[ 59-88-1 ]
[ 1218-69-5 ]
[ 86245-87-6 ]

References: [1]European Journal of Inorganic Chemistry,2004,p. 4177 - 4192.
[2]Chemistry - An Asian Journal,2015,vol. 10,p. 2368 - 2379.

22
[ 1218-69-5 ]
[ 20237-92-7 ]

References: [1]Zeitschrift fur Chemie,1981,vol. 21,p. 261.
[2]Zeitschrift fur Chemie,1981,vol. 21,p. 261.

23
[ 1218-69-5 ]
[ 86259-35-0 ]

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.

24
[ 1218-69-5 ]
[ 86245-88-7 ]

References: [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 332 - 336.
Khimiya Geterotsiklicheskikh Soedinenii,1983,p. 406 - 410.

25
[ 1218-69-5 ]
[ 40594-29-4 ]
[ 201530-46-3 ]