[ CAS No. 201530-41-8 ] {[proInfo.proName]}

Name: 201530-41-8|4-(3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid|98%
Brand: Ambeed
SKU: A340437
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Quality Control of [ 201530-41-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 201530-41-8 ]

SDS Specification

Alternatived Products of [ 201530-41-8 ]

Product Details of [ 201530-41-8 ]

CAS No. :	201530-41-8	MDL No. :	MFCD09951804
Formula :	C₂₁H₁₅N₃O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BOFQWVMAQOTZIW-UHFFFAOYSA-N
M.W :	373.36	Pubchem ID :	214348
Synonyms :	ICL 670;ICL670A;Desifer.;Defrijet;Desirox;Deferasirox. Brand name: Exjade;CGP-72670

Calculated chemistry of [ 201530-41-8 ]

Physicochemical Properties

Num. heavy atoms :	28
Num. arom. heavy atoms :	23
Fraction Csp3 :	0.0
Num. rotatable bonds :	4
Num. H-bond acceptors :	6.0
Num. H-bond donors :	3.0
Molar Refractivity :	103.24
TPSA :	108.47 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.88 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.58
Log Po/w (XLOGP3) :	3.8
Log Po/w (WLOGP) :	3.71
Log Po/w (MLOGP) :	2.81
Log Po/w (SILICOS-IT) :	2.42
Consensus Log Po/w :	3.07

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-4.89
Solubility :	0.00478 mg/ml ; 0.0000128 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.77
Solubility :	0.000631 mg/ml ; 0.00000169 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.76
Solubility :	0.000655 mg/ml ; 0.00000175 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.95

Safety of [ 201530-41-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 201530-41-8 ]

* 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 [ 201530-41-8 ]
Downstream synthetic route of [ 201530-41-8 ]

[ 201530-41-8 ] Synthesis Path-Upstream 1~23

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[ 1311284-26-0 ]
[ 14685-90-6 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: at 20℃; Stage #2: With hydrogenchloride In ethanol; water	.2 mol of compound II (X = SiMe₃) was added to a solution of 4- hydrazinobenzoic acid ethyl ester (0.3 mol) in 150 ml of ethanol abs. The mixture was stirred at room temperature under TLC monitoring. After completion of the reaction, water was added until some perturbation (i.e. a first sign of precipitation) was observed. The mixture was concentrated to a total volume of 50percent under reduced pressure and aqueous 6 M HC1 (40 mL) was added. The mixture was stirred until TLC analysis indicated complete deprotection of protecting groups and deferasirox formation. The resulting solid was filtered, washed with mixture ethanol-water and dried for 24 h in vacuum (85percent yield). The solid was allowed to stand exposed to the air to form the monohydrate.

Reference： [1] Patent: WO2011/70560, 2011, A1, . Location in patent: Page/Page column 61

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Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In ethanol for 2 h; 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 50percent 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, 99percent) as dark yellow solid.
93%	With propionic acid In chlorobenzene at 130℃; for 1 h; Heating / reflux	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. 93percent of the theory, with an HPLC content of 95.41percent and a melting temperature of 253 to 262 ⁰C.
91%	With propionic acid In 1-methyl-pyrrolidin-2-one at 120℃; for 1 h;	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 percent of the theory, with an HPLC content of 92.9percent and a melting temperature of 250 to 261 ⁰C.

87%	at 132℃; for 2 h; Heating / reflux	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. 87percent of the theory, with HPLC purity above 99.4percent 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. 86percent of the theory, with an HPLC purity above 99.8percent 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. 82percent of the theory, with HPLC purity above 99.8percent. Melting temperature: 264 to 266 ⁰C.
87%	With propionic acid In toluene at 110℃; for 2 h; Heating / reflux	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 (87percent of the theory), which contains 97.1percent 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 (67percent of the theory) is obtained with a purity of 98.5 percent and a melting temperature of 260 to 264 ⁰C.
86%	for 3 h; 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 (86percent 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 2 h; Heating / reflux	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. 84percent of the theory, with an HPLC purity of 99.7percent and a melting temperature of 258 to 263 ⁰C.
82.5%	Heating / reflux	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 percent.
81%	With propionic acid In N,N-dimethyl-formamide at 150℃; for 1.5 h;	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. 81percent of the theory, with an HPLC purity of 93percent and a melting temperature of 255 to 262 ⁰C.
80%	With triethylamine In ethanol for 2 h; 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 50percent 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 =80percent). (0011) IR (KBr, cm⁻¹) ν 33,317, 2540, 1680 (ν_C=O), 1607, 1517, 1495, 1431, 1351, 1221, 988, 752. ¹H NMR (CD₃COCD₃, ppm): δ=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) δ=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 7 h;	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- 30°C. To the above contents 4- hydrazino benzoic acid (20.03gm) 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 lhr at 25 - 30°C. The reaction mass was filtered and washed with methylene chloride (30.0ml). Dried the compound at 60-65°C. Yield: 79.0percent.
77%	Stage #1: at 77℃; for 2 h; Industry scale Stage #2: at 80℃; Industry scale	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.percent 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.percent 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 3percent 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 77percent in this step. The product is analysed by HPLC, determining a purity of more than 99.8percent. 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%	at 100℃; for 1 h;	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. 60percent of the theory, with an HPLC content of 99.3percent and a melting temperature of 259 to 263 ⁰C.
55%	With trichloroacetic acid In toluene at 110℃; for 3 h;	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. 55percent of the theory, with an HPLC content of 99.56percent and a melting temperature of 258 to 262 ⁰C.
50%	With propionic acid In 2-methyltetrahydrofuran at 98℃; for 2 h; Heating / reflux	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"/>50percent of the theory, with an HPLC purity of 95.3percent and a melting temperature of 255 to 262 ⁰C.
49%	at 115℃; for 2 h; Heating / reflux	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. 49percent of the theory, with an HPLC content of 94percent 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. 29percent of the theory, with a purity of 98.5percent 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. 17percent of the theory, with a purity above 99.0percent. Melting temperature: 258 to 263 ⁰C.

Reference： [1] Patent: US2016/296629, 2016, A1, . Location in patent: Paragraph 0062
[2] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 11-12
[3] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 10-11
[4] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 7
[5] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 8
[6] Organic Preparations and Procedures International, 2015, vol. 47, # 6, p. 483 - 489
[7] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 9
[8] Patent: WO2008/94617, 2008, A2, . Location in patent: Page/Page column 12
[9] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 10
[10] European Journal of Inorganic Chemistry, 2004, # 21, p. 4177 - 4192
[11] New Journal of Chemistry, 2016, vol. 40, # 3, p. 2696 - 2703
[12] European Journal of Pharmacology, 2016, vol. 781, p. 209 - 217
[13] Patent: WO2012/25935, 2012, A2, . Location in patent: Page/Page column 7
[14] Patent: WO2012/131017, 2012, A1, . Location in patent: Page/Page column 7-8
[15] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 11
[16] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 11
[17] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 8-9
[18] Patent: WO2009/94956, 2009, A1, . Location in patent: Page/Page column 9-10
[19] Patent: US6465504, 2002, B1,
[20] Patent: WO2009/147529, 2009, A1, . Location in patent: Page/Page column 15
[21] Patent: WO2010/23685, 2010, A2, . Location in patent: Page/Page column 6; 9
[22] Patent: WO2011/21218, 2011, A2, . Location in patent: Page/Page column 21
[23] Patent: US2011/97413, 2011, A1, . Location in patent: Page/Page column 9
[24] Patent: US2011/171138, 2011, A1, . Location in patent: Page/Page column 6
[25] Patent: WO2012/69946, 2012, A1, . Location in patent: Page/Page column 4-5
[26] Synthetic Communications, 2012, vol. 42, # 21, p. 3200 - 3210
[27] Patent: US2013/338356, 2013, A1, . Location in patent: Paragraph 0021
[28] Patent: US2014/39199, 2014, A1, . Location in patent: Paragraph 0044
[29] Patent: CN108727287, 2018, A, . Location in patent: Paragraph 0023; 0032-0034

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Yield	Reaction Conditions	Operation in experiment
85%	With trifluoroacetic acid In ethanol for 4 h; Reflux	Disalicylimide (4) (3.7 g, 14.32 mmol) and 4-hydrazinobenzoic acid (2.6 g, 17.14 mmol) were suspended in ethanol (50 ml) and refluxed, adding TFA in portions until most of the reagents were dissolved ( 6percent v/v), monitoring the reaction progress by HPLC. After 4h no more starting material was present. The mixture was cooled and concentrated. After cooling the precipitate was filtered. The solid was recrystallized from ethanol-water, filtered, washed with mixture ethanol-water and dried for 24 h in vacuum to give desired compound with 85percent yield.^.H NMR (400 MHz, DMSO- d₆): δ: 6.87 (d, J=8.4 Hz, 1H), 7.045-6.97 (m, 3H), 7.24 (m, 2H), 7.405 (qd, 3=7.6, 1.6 Hz, 2H), 7.558 (d, J=10 Hz, 3H), 7.98 (d, J=8.4 Hz, 2H), 8.059 (dd, 5=7.6, 2 Hz, 1H), 10.059 (s, OH), 10.812 (s, OH). EI-MS calcd for C₂₁H₁₅N₃0₄ MW 373.11, found mlz 373.11Anal Calcd for C₂₁Hi₅N₃04 (373.36): C, 67.56; H, 4.05; N, 11.25 Found: C, 67.48; H, 4.0; N, 10.98.

Reference： [1] Patent: WO2011/70560, 2011, A1, . Location in patent: Page/Page column 62

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[ 1642597-21-4 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
1.7g	With 2-(diethylamine)ethanethiol; sodium t-butanolate In N,N-dimethyl-formamide at 150℃; for 2 h; Inert atmosphere	To a solution of 2-(diethylamino)ethanethiol (2.7 g,20 mmol) in dimethylformamide (27 mL) under nitrogen atmosphere was added sodium tert-butoxide(3.0 g, 0.3 mmol) at 0°C. Into the resulting solution, methyl 4-(3,5-bis(2-methoxyphenyl)-1H-1,2,4-triazol-1-yl) benzoate (5, 2.1 g, 5.1 mmol) was added and stirred at 150°C for 2 h during which TLC showed the completion of the reaction. It was cooled to 25°C followed by the addition of water (150 mL). It was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford Deferasirox (1.7 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 6.87 (d, 1H),7.045-6.97 (m, 3H), 7.24 (m, 2H), 7.405 (qd, Hz, 2H),7.558 (d, 3H), 7.98 (d, 2H), 8.059 (dd, 2 Hz, 1H),10.059 (s, OH), 10.812 (s, OH).

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 5, p. 610 - 618

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Reference： [1] Patent: WO2011/21218, 2011, A2, . Location in patent: Page/Page column 24

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Reference： [1] Angewandte Chemie - International Edition, 2010, vol. 49, # 2, p. 325 - 328

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Yield	Reaction Conditions	Operation in experiment
310 g	at 90℃; for 2 h;	To about 200 g of 2-(2-Hydroxyphenyl)benz[e]oxazin-4-one (Formula-4) in water (3 L), about 150 g of 4-hydrozenobenzoic acid (Formula-5) is added and heated at 90° C. for 2 h. The suspension is cooled to ambient temperature for complete precipitation to obtain the precipitate. Thereafter, the precipitate is filtered and washed with isopropanol (250 ml) twice, and sucked dry to obtain deferasirox (Formula-1) (310 g) having pale yellow colour.

Reference： [1] Patent: US2016/24025, 2016, A1, . Location in patent: Paragraph 0082-0083

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Yield	Reaction Conditions	Operation in experiment
125 g	Stage #1: for 2 h; Reflux Stage #2: With hydrogenchloride In isopropyl alcohol	To about 100 g of 2-(2-Hydroxyphenyl)benz[e]oxazin-4-one sodium salt in isopropanol (1.5 L), about 70 g of 4-hydrozenobenzoic acid (Formula-5) is added and refluxed for about 2 h. After completion of the reaction, the reaction mixture is cooled to ambient temperature for complete precipitation. The precipitated solid is isolated by filtration. The obtained solid is washed with isopropanol (100 ml). The resulting solid is suspended in isopropanol and acidified to pH 4 using hydrochloric acid. The reaction mixture is stirred for complete precipitation, to obtain the precipitate having crude Deferasirox. The crude Deferasirox is isolated by filtration of the precipitate and drying the precipitate under vacuum to obtain semi-pure deferasirox (Formula-1) (125 g) having greyish yellow colour.

Reference： [1] Patent: US2016/24025, 2016, A1, . Location in patent: Paragraph 0081

9
[ 69-72-7 ]
[ 201530-41-8 ]

Reference： [1] Patent: WO2011/21218, 2011, A2,
[2] Patent: US2011/97413, 2011, A1,
[3] Patent: WO2012/25935, 2012, A2,
[4] Patent: WO2012/131017, 2012, A1,
[5] Synthetic Communications, 2012, vol. 42, # 21, p. 3200 - 3210
[6] Patent: WO2011/70560, 2011, A1,
[7] Patent: US2016/24025, 2016, A1,
[8] Patent: US2016/24025, 2016, A1,
[9] Patent: US2016/296629, 2016, A1,
[10] Patent: CN108727287, 2018, A,

10
[ 1266741-05-2 ]
[ 201530-41-8 ]

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 5, p. 610 - 618
[2] Inorganica Chimica Acta, 2012, vol. 393, p. 294 - 303

11
[ 65-45-2 ]
[ 201530-41-8 ]

Reference： [1] European Journal of Inorganic Chemistry, 2004, # 21, p. 4177 - 4192
[2] Patent: WO2011/21218, 2011, A2,
[3] Patent: US2011/97413, 2011, A1,
[4] Synthetic Communications, 2012, vol. 42, # 21, p. 3200 - 3210
[5] Patent: US2016/296629, 2016, A1,
[6] Patent: CN108727287, 2018, A,

12
[ 619-67-0 ]
[ 21958-32-7 ]
[ 201530-41-8 ]

Reference： [1] MedChemComm, 2016, vol. 7, # 12, p. 2290 - 2298
[2] MedChemComm, 2017, vol. 8, # 10, p. 1953 - 1964

13
[ 1414867-91-6 ]
[ 623-05-2 ]
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Reference： [1] Inorganica Chimica Acta, 2012, vol. 393, p. 294 - 303

14
[ 619-67-0 ]
[ 201530-41-8 ]

Reference： [1] Angewandte Chemie - International Edition, 1999, vol. 38, # 17, p. 2568 - 2570

15
[ 1441-87-8 ]
[ 201530-41-8 ]

Reference： [1] Patent: WO2011/70560, 2011, A1,
[2] Patent: US2016/24025, 2016, A1,
[3] Patent: US2016/24025, 2016, A1,

16
[ 4510-12-7 ]
[ 201530-41-8 ]

Reference： [1] Inorganica Chimica Acta, 2012, vol. 393, p. 294 - 303

17
[ 1218-69-5 ]
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Reference： [1] Inorganica Chimica Acta, 2012, vol. 393, p. 294 - 303

18
[ 1414867-90-5 ]
[ 623-05-2 ]
[ 201530-41-8 ]

Reference： [1] Inorganica Chimica Acta, 2012, vol. 393, p. 294 - 303

19
[ 36850-04-1 ]
[ 201530-41-8 ]

Reference： [1] Patent: WO2011/70560, 2011, A1,

20
[ 1642597-20-3 ]
[ 201530-41-8 ]

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 5, p. 610 - 618

21
[ 106724-85-0 ]
[ 201530-41-8 ]

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 5, p. 610 - 618

22
[ 1642597-22-5 ]
[ 201530-41-8 ]

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 5, p. 610 - 618

23
[ 1642597-27-0 ]
[ 99768-12-4 ]
[ 201530-41-8 ]

Reference： [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 5, p. 610 - 618

[ 201530-41-8 ] Synthesis Path-Downstream 1~88

1
[ 619-67-0 ]
2-(2-hydroxyphenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one [ No CAS ]
[ 201530-41-8 ]

Reference： [1]Angewandte Chemie - International Edition,1999,vol. 38,p. 2568 - 2570

2
[ 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].

Reference： [1]Patent: US2016/296629,2016,A1 .Location in patent: Paragraph 0062
[2]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 11-12
[3]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 10-11
[4]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 7
[5]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 8
[6]Organic Preparations and Procedures International,2015,vol. 47,p. 483 - 489
[7]Advanced synthesis and catalysis,2020
[8]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 9
[9]Patent: WO2008/94617,2008,A2 .Location in patent: Page/Page column 12
[10]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 10
[11]European Journal of Inorganic Chemistry,2004,p. 4177 - 4192
[12]New Journal of Chemistry,2016,vol. 40,p. 2696 - 2703
[13]European Journal of Pharmacology,2016,vol. 781,p. 209 - 217
[14]Patent: WO2012/25935,2012,A2 .Location in patent: Page/Page column 7
[15]Patent: WO2012/131017,2012,A1 .Location in patent: Page/Page column 7-8
[16]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 11
[17]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 11
[18]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 8-9
[19]Patent: WO2009/94956,2009,A1 .Location in patent: Page/Page column 9-10
[20]Patent: US6465504,2002,B1
[21]Patent: WO2009/147529,2009,A1 .Location in patent: Page/Page column 15
[22]Patent: WO2010/23685,2010,A2 .Location in patent: Page/Page column 6; 9
[23]Patent: WO2011/21218,2011,A2 .Location in patent: Page/Page column 21
[24]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 9
[25]Patent: US2011/171138,2011,A1 .Location in patent: Page/Page column 6
[26]Patent: WO2012/69946,2012,A1 .Location in patent: Page/Page column 4-5
[27]Synthetic Communications,2012,vol. 42,p. 3200 - 3210
[28]Patent: US2013/338356,2013,A1 .Location in patent: Paragraph 0021
[29]Patent: US2014/39199,2014,A1 .Location in patent: Paragraph 0044
[30]Patent: CN108727287,2018,A .Location in patent: Paragraph 0023; 0032-0034
[31]Patent: WO2019/16637,2019,A1 .Location in patent: Page/Page column 8-9
[32]Angewandte Chemie - International Edition,2019,vol. 58,p. 8773 - 8778
Angew. Chem.,2019,vol. 131,p. 8865 - 8870,6

3
[ 201530-41-8 ]
[ 872005-50-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; In dichloromethane; for 22h;Reflux;	Thionyl chloride (0.20 mL, 2.687 mmol) was added to <strong>[201530-41-8]deferasirox</strong> (2Error. Reference source not found.) (0.100 g, 0.268 mmol) in DCM (20.00 mL), and solution refluxed for 22 h. The residue was concentrated in vacuo to yield 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoyl chloride (5) as dark brown solid (0.104 g, 0.268 mmol, 99%)

Reference： [1]Patent: US2016/296629,2016,A1 .Location in patent: Paragraph 0068-0069
[2]Journal of Organic Chemistry,2005,vol. 70,p. 9686 - 9692

4
[ 65-45-2 ]
[ 201530-41-8 ]

Reference： [1]European Journal of Inorganic Chemistry,2004,p. 4177 - 4192
[2]Patent: WO2011/21218,2011,A2
[3]Patent: US2011/97413,2011,A1
[4]Synthetic Communications,2012,vol. 42,p. 3200 - 3210
[5]Patent: US2016/296629,2016,A1
[6]Patent: CN108727287,2018,A
[7]Angewandte Chemie - International Edition,2019,vol. 58,p. 8773 - 8778
Angew. Chem.,2019,vol. 131,p. 8865 - 8870,6
[8]Advanced Synthesis and Catalysis,2020,vol. 362,p. 2459 - 2465

5
[ 69-72-7 ]
diazotized 5-nitro-<1>naphthylamine [ No CAS ]
[ 201530-41-8 ]

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

6
[ 109-01-3 ]
[ 26189-59-3 ]
[ 201530-41-8 ]
{4-[3,5-bis(2-hydroxy-phenyl)-[2,4]triazol-1-yl]-phenyl}-(4-methylpiperazin-1-yl)methanone [ No CAS ]
[ 201530-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	EXAMPLE 7 {4-[3,5-Bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-phenyl}-(4-methylpiperazin-1-yl)-methanone 3 g of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid (Example 5) and 1.25 ml of 1-chloro-N,N-2-trimethyl-1-propen-1-amine are stirred for 2 h in 50 ml of tetrahydrofuran. 2.2 ml of triethylamine and 1 ml of N-methylpiperazine are added and the mixture is stirred at room temperature for 48 h. It is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, {4-[3,5-bis(2-hydroxy-phenyl)-[2,4]triazol-1-yl]-phenyl}-(4-methylpiperazin-1-yl)methanone remains as colorless crystals of m.p. 226-229 C.

Reference： [1]Patent: US6465504,2002,B1

7
[ 201530-41-8 ]
a complex of gallium and 4-[3,5-bis(2-hydroxyphenyl)-[1,2,3]triazol-1-yl]benzoic acid [ No CAS ]

Reference： [1]Patent: WO2007/51773,2007,A1 .Location in patent: Page/Page column 13

8
Iron(III) nitrate nonahydrate [ No CAS ]
[ 201530-41-8 ]
[Fe(4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid^(3-))2]^(3-) [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2004,vol. 87,p. 3021 - 3034

Yield	Reaction Conditions	Operation in experiment
91.9%	With pyrographite; In isopropyl alcohol; at 25 - 85℃;Purification / work up;	Example 3: Purification of <strong>[201530-41-8]Deferasirox</strong>.[0019] Take Isopropyl alcohol (900.0 ml) and <strong>[201530-41-8]Deferasirox</strong> crude (30.0 gm) at 25 - 30C. Stir the contents for 10 min at 25 -30C. Reaction mass was heated reflux temperature (80 -85C) and maintained for 30 min at reflux temperature. Activated carbon (3.0g) was added to the above reaction mass at reflux temperature. Reaction mass was maintained for 30 min at reflux temperature. The reaction mass was filtered through hyflow bed at hot condition and washed with isopropyl alcohol (30.0 ml). Isopropyl alcohol was distilled off until the 150 ml solvent is remained in the flask. Reaction mass was stirred for 30 min at 25-30C. The mass was filtered and washed with isopropyl alcohol (30.0 ml). Methanol (150.0ml) was added to the above wet compound and stirred for 10 min at 25 - 30C. The contents were heated to reflux temperature (65 -70C) and maintained the contents for 3hr at reflux temperature. Reaction mass was cooled to 25 -30C and stirred for lhr at 25 -30C. The reaction mass was filtered and washed with methanol (30.0 ml). Dried the compound at 60-65C. Yield: 91.0%, Purity: >99.9%
	In methanol; for 0.25h;active carbon;Purification / work up;	A mixture of 1.01 g (2.71 mmol, 99.45 % HPLC) of <strong>[201530-41-8]deferasirox</strong> in 50 ml of methanol is dissolved at the boiling temperature. 0.2 g of active carbon is added to the solution and filtration is performed, after 15 minutes. The filtrate is concentrated to achieve crystallization. The crystals, obtained by cooling, are aspirated and washed with 10 ml of methanol. After drying, 0.74 g of re-crystallized <strong>[201530-41-8]deferasirox</strong> is obtained, i.e. 74% of the theory, with an HPLC content of 99.9% and a melting temperature of 264 to 266 0C.
		Crude <strong>[201530-41-8]deferasirox</strong> (3.33 g, 8.919 mmol, obtained in the above reference example) was suspended in water (17 ml) at 22 to 25C, and then a solution of sodium hydroxide (0.392 g, 9.8 mmol) in water (5.0 ml) was added drop wise to it. The mixture was heated to 55C to provide a clear solution, followed by cooling to 25C. Acetone (25 ml) was added to above solution and pH was adjusted to 2.0 to 2.5 with a concentrated hydrochloric acid solution (1.1 ml) at 22 to 250C. The solid precipitate was further stirred for 30 minutes. The precipitated solid was filtered and dried to produce 2.9 g of pure <strong>[201530-41-8]deferasirox</strong> (HPLC purity: 99.99%; content of 4-hydrazinobenzoic acid impurity: not detected).

	In isopropyl alcohol; at 80 - 85℃;Activated carbon;Purification / work up;	50 gms of 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid was dissolved in 1250 ml of isopropyl alcohol and maintained for 60 to 90 minutes at 80-85C. 0.5 gm of activated carbon was added to the reaction mass and maintained for 30 minutes at the same temperature. The reaction mass was then filtered through high flow bed and washed with 50 ml of isopropyl alcohol, which was subsequently distilled off completely and charged with 250 ml of acetone. The reaction mass was then cooled to 15-250C and maintained for 60 minutes and dried at 50-60C under vacuum for 4-6 hours to produce 45 gms of pure 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid. Further 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, A- triazol-1-yl) benzoic acid was suspended in methanol 250 ml and heated to reflux for 3-5 hours. Subsequently resultant mixture was cooled and filtered to obtain pure 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid.
		The <strong>[201530-41-8]deferasirox</strong> compound of formula- 1 was purified in a similar manner to example-15 except that bases like triethanolamine, diisopropylethylamine and di-n- propylamine was used in place of triethyl amine and the corresponding results are tabulated below.
		Example 5Crude <strong>[201530-41-8]deferasirox</strong> (3.33 g, 8.919 mmol, obtained in the above reference example) was suspended in water (17 ml) at 22 to 25 C. and a solution of sodium hydroxide (0.392 g, 9.8 mmol) in water (5 ml) was added drop wise to it. The mixture was heated to 55 C. to provide a clear solution, followed by cooling to 25 C. Methanol (25 ml) was added to the clear solution. The resulting mixture was followed by drop wise addition of concentrated hydrochloric acid (1.1 ml) at 22 to 25 C. The precipitated solid was further stirred for 30 minutes. The resulting solid was filtered and dried to produce 3.3 g of pure <strong>[201530-41-8]deferasirox</strong> (HPLC purity: 99.99%; content of 4-hydrazinobenzoic acid impurity: not detected).Level of organic volatile impurities: methanol: 690 ppm.
		The raw product obtained in example 3 is further purified by placing in a reactor, together with 38.4 kg of 3 wt.% toluene/ethanol mixture, 1 3 kg of distilled water, and 1 .44 kg of a 30 wt.% solution of ammonia in water. The mixture is heated under reflux (approximately 78 C), so as to achieve complete dissolution of the solid. 380 g of decolourising carbon Picapure SP Pharma suspended in water is added, and the suspension is maintained with stirring under reflux for 30 minutes; the suspension is then cooled to 60 C and filtered. The filtered solution is then put into a reactor, heated under reflux, and 3.94 kg of 80 wt. % acetic acid is added. Precipitation of a solid occurs. The precipitated mass is stirred under reflux (at approximately 80 C) for 30 minutes, then it is cooled to ambient temperature, centrifuged separating the solid, and finally washed with the mixture formed from 19.2 kg of distilled water and 4.8 kg of ethanol/toluene as described previously. The solid obtained is dried overnight at 90 C, resulting in 8 kg of a crystalline product, which analyses confirm as being crystalline <strong>[201530-41-8]deferasirox</strong> of HPLC purity greater than 99,98%. The yield from purification is equal to approximately 83% relative to raw <strong>[201530-41-8]deferasirox</strong>.

10
[ 619-67-0 ]
N-(2-Hydroxybenzoyl)-2-hydroxybenzamidin [ No CAS ]
[ 201530-41-8 ]

Reference： [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 325 - 328

11
[ 138-14-7 ]
[ 201530-41-8 ]
[ 1149568-62-6 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 1370 - 1382

12
[ 74-89-5 ]
[ 201530-41-8 ]
[ 1266741-01-8 ]

Yield	Reaction Conditions	Operation in experiment
	In water; ethyl acetate; at 25 - 30℃; for 2h;	Added 30 ml of ethyl acetate to the crude <strong>[201530-41-8]deferasirox</strong> (3 grams) followed by 40% aqueous methyl amine (0.74ml) at 25-30C. Stirred the reaction mixture for 2 hours at 25- 30C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material for 5 hours. Added 40 ml of acetone to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25- 35C. Stirred the reaction mixture for 6 hours at 25-35C. Filtered the precipitated solid and dried the material at 50-55C to get the title compound.Yield: 3.1 grams.

Reference： [1]Patent: WO2011/21218,2011,A2 .Location in patent: Page/Page column 22

13
[ 109-73-9 ]
[ 201530-41-8 ]
[ 1266741-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 25 - 30℃; for 2h;	Added 100 ml of ethyl acetate to the crude <strong>[201530-41-8]deferasirox</strong> (10 grams) followed by n-butyl amine (2 ml) at 25-30C.Stirred the reaction mixture for 2 hours at 25-30C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material for 6 hours. Added * 100 ml of ethyl acetate to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35C. Stirred ' the reaction mixture for 6 hours at 25-35C. Filtered the precipitated solid and dried the- material at 50-55C to get the title compound.Yield: 9.8 grams

Reference： [1]Patent: WO2011/21218,2011,A2 .Location in patent: Page/Page column 23

14
[ 69-72-7 ]
[ 201530-41-8 ]

Reference： [1]Patent: WO2011/21218,2011,A2
[2]Patent: US2011/97413,2011,A1
[3]Patent: WO2012/25935,2012,A2
[4]Patent: WO2012/131017,2012,A1
[5]Synthetic Communications,2012,vol. 42,p. 3200 - 3210
[6]Patent: WO2011/70560,2011,A1
[7]Patent: US2016/24025,2016,A1
[8]Patent: US2016/24025,2016,A1
[9]Patent: US2016/296629,2016,A1
[10]Patent: CN108727287,2018,A

15
[ 75-31-0 ]
[ 201530-41-8 ]
[ 1266741-02-9 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 25 - 30℃; for 2h;	Added 100 ml of ethyl acetate to the crude <strong>[201530-41-8]deferasirox</strong> (10 grams) followed by isopropyl amine (1.5 ml) at 25-30C. Stirred the reaction mixture for 2 hours at 25-30C. Filtered the precipitated solid and washed with ethyl acetate. Added 100 ml of ethyl acetate to the above solid and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35C. Stirred the reaction mixture for 6 hours at 25-35C. Filtered the precipitated solid and dried the material at 50-55C to get the title compound.Yield: 9.4 grams.

Reference： [1]Patent: WO2011/21218,2011,A2 .Location in patent: Page/Page column 23

16
[ 101-83-7 ]
[ 201530-41-8 ]
[ 1266741-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 25 - 30℃; for 2h;	Added 50 ml of ethyl acetate to the crude <strong>[201530-41-8]deferasirox</strong> (5 grams) followed by dicyclohexylamine (2 ml) at 25-30C. Stirred the reaction mixture for 2 hours at 25-30C. Filtered the precipitated solid and washed it with ethyl acetate. Dried the solid material for 6 hours. Added 60 ml of toluene to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35C. Stirred the reaction mixture for 6 hours at 25-35C. Filtered the precipitated solid and dried the material at 50-550C to get the title compound.Yield: 4.9 grams

Reference： [1]Patent: WO2011/21218,2011,A2 .Location in patent: Page/Page column 23

17
[ 67-56-1 ]
[ 201530-41-8 ]
[ 1266741-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; for 1h;Reflux;	A mixture \|of <strong>[201530-41-8]deferasirox</strong> (5 grams), methanol (100 ml) and sulphuric acid (0.5 ml) was heated to reflux temperature. The reaction mixture was stirred at reflux for an hour. The reaction mixture was cooled to 0-50C and stirring for 30 minutes. The solid was filtered and dried to get the title compound.Yield: 4.8 grams
	With sulfuric acid;Reflux;	In a 100 mL three-necked flask to which 25 mL of anhydrous methanol was added, 0.50 g of 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid was added. a few drops of concentrated sulfuric acid, Heating and refluxing for 8 hours, After the reaction is over, Evaporate the reaction solution under reduced pressure. The residue was purified by column chromatography to give a white product. Melting point 174-175 C.

Reference： [1]Patent: US2016/296629,2016,A1 .Location in patent: Paragraph 0092
[2]Synthetic Communications,2012,vol. 42,p. 3200 - 3210
[3]Angewandte Chemie - International Edition,2019,vol. 58,p. 8773 - 8778
Angew. Chem.,2019,vol. 131,p. 8865 - 8870,6
[4]Patent: WO2011/21218,2011,A2 .Location in patent: Page/Page column 25
[5]Patent: CN108727287,2018,A .Location in patent: Paragraph 0035-0037

18
[ 1266741-01-8 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; water; for 0.5h;pH ~ 2;	Deferasirox methyl amine salt(2.0 grams) was taken in methanol (20ml) and added water (40ml) and stirred for 15 minutes. The pH of the solution was adjusted to around 2 using dilute hydrochloric acid and stirred the solution for 30 minutes. Filtered the precipitated solid washed with methanol and dried to provide pure deferasirox.Yield: 1.6 grams; HPLC Purity: 99.90 %

Reference： [1]Patent: WO2011/21218,2011,A2 .Location in patent: Page/Page column 24

19
[ 124-40-3 ]
[ 201530-41-8 ]
[ 1192228-24-2 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 78 - 80℃;	Example 11; Preparation of Dimethylamine Salt of <strong>[201530-41-8]Deferasirox</strong>4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (2 gm) was suspended in isopropyl alcohol (80 ml) at 22-25 C. and further refluxed at 78-80 C. to get a clear solution. This was followed by the drop wise addition of dimethylamine (0.679 ml) at 78-80 C. The reaction mixture was then cooled at 25 C. and the resulting solid was filtered and further dried under vacuum at 70-80 C. to produce 2 gm of crystalline <strong>[201530-41-8]deferasirox</strong> dimethylamine salt (Purity by HPLC: 99.98%).

Reference： [1]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 10

20
[ 121-44-8 ]
[ 201530-41-8 ]
[ 1198306-76-1 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 78 - 80℃;	Example 9; Preparation of Triethylamine Salt of <strong>[201530-41-8]Deferasirox</strong>4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (1 gm) was suspended in isopropyl alcohol (40 ml) at 22-25 C. and refluxed at 78-80 C. to get a clear solution. This was followed by the drop wise addition of triethylamine (0.41 ml) at 78-80 C. The resulting mass was cooled at 25 C. and the resulting solid was filtered and further dried under vacuum at 70-80 C. to produce 1.22 gm of crystalline <strong>[201530-41-8]deferasirox</strong> triethylamine salt (Purity by HPLC: 99.97%).

Reference： [1]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 10

21
[ 75-64-9 ]
[ 201530-41-8 ]
[ 1192228-25-3 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol;Reflux;	Example 10; Preparation of tert-butylamine Salt of <strong>[201530-41-8]Deferasirox</strong>4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (2 gm) was suspended in isopropyl alcohol (80 ml) and heated at 78-80 C. to get a clear solution. This was followed by the drop wise addition of tert-butylamine (0.564 ml) at reflux temperature. The reaction mixture was cooled at 25 C. and the resulting solid was filtered and further dried under vacuum at 70-80 C. to produce 0.7 gm of crystalline <strong>[201530-41-8]deferasirox</strong> tert-butylamine salt (Purity by HPLC: 99.97%).

Reference： [1]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 10

22
[ 201530-41-8 ]
sodium 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; at 22 - 55℃;	Example 4; Preparation of <strong>[201530-41-8]Deferasirox</strong> Sodium Salt4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (1 gm) was suspended in water (5 ml). This was followed by the drop wise addition of a solution of sodium hydroxide (0.117 gm) in water (2 ml) at 22-25 C. The reaction mixture was heated at 50-55 C. to form a clear solution. The resulting solution was concentrated under vacuum. This was followed by the addition of water (3 ml) and heating of the resulting mass to get a clear solution which was further cooled at 0 C. The resulting solid was filtered and further dried under vacuum at 80-90 C. to produce 0.65 gm of crystalline <strong>[201530-41-8]deferasirox</strong> sodium salt (Purity by HPLC: 99.99%).

Reference： [1]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 9

23
[ 201530-41-8 ]
potassium 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In water; at 22 - 55℃;	Example 5; Preparation of <strong>[201530-41-8]Deferasirox</strong> Potassium Salt4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (2 gm) was suspended in water (15 ml) at 22-25 C. This was followed by the drop wise addition of a solution of potassium hydroxide (0.33 gm) in water (2 ml) at 22-25 C. The resulting mass was heated at 50-55 C. to get a clear solution. The resulting solution was concentrated under vacuum and followed by the addition of isopropyl alcohol (20 ml). The reaction mixture was further heated at 55 C. for 30 minutes and then cooled at 0 C. The resulting solid was filtered and further dried under vacuum at 80-90 C. to produce 1.4 gm of crystalline <strong>[201530-41-8]deferasirox</strong> potassium salt (Purity by HPLC: 99.97%).

Reference： [1]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 9

24
[ 201530-41-8 ]
magnesium 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Method-II:4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (1 gm) was suspended in methanol (10 ml) at 22-25 C. This was followed by the drop wise addition of a solution of sodium hydroxide (0.117 gm) in methanol (5 ml) at 22-25 C. The reaction mixture was heated at 50-55 C. to get a clear solution and followed by the addition of a solution of magnesium chloride (0.279 gm) in water (1 ml). The resulting solid was filtered and further dried under vacuum at 65-70 C. to produce 0.5 gm of crystalline <strong>[201530-41-8]deferasirox</strong> magnesium salt (Purity by HPLC: 99.81%).

Reference： [1]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 9

25
[ 201530-41-8 ]
calcium 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 7; Preparation of <strong>[201530-41-8]Deferasirox</strong> Calcium Salt4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (2 gm) was suspended in water (5 ml) at 22-25 C. and followed by the drop wise addition of a solution of sodium hydroxide (0.235 gm) in water (5 ml) at 22-25 C. The resulted mass was heated at temperature 50-55 C. to get a clear solution. This was followed by the addition of a solution of calcium chloride (0.654 gm) in water (6 ml) and the resulting solid was filtered and further dried under vacuum at 80-90 C. to produce 1.27 gm of crystalline <strong>[201530-41-8]deferasirox</strong> calcium salt (Purity by HPLC: 99.97%).

Reference： [1]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 9-10

26
[ 201530-41-8 ]
zinc 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 8; Preparation of <strong>[201530-41-8]Deferasirox</strong> Zinc Salt4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (2 gm) was suspended in water (20 ml) at 22-25 C. and followed by the drop wise addition of a solution of sodium hydroxide (0.235 gm) in water (5 ml) at 22-25 C. The reaction mass was heated at temperature 50-55 C. to get a clear solution. This was followed by the addition of a solution of zinc chloride (0.801 gm) in water (4 ml) and the resulting solid was filtered and further dried under vacuum at 80-90 C. to produce 2 gm of crystalline <strong>[201530-41-8]deferasirox</strong> zinc salt (Purity by HPLC: 99.94%).

Reference： [1]Patent: US2011/97413,2011,A1 .Location in patent: Page/Page column 10

27
[ 1300740-29-7 ]
[ 201530-41-8 ]
[ 1300740-33-3 ]

Yield	Reaction Conditions	Operation in experiment
81%		General procedure: A solution of carboxylic acid (1.1 equiv/equiv NH2 group), HOBt (1.1 equiv/equiv NH2 group), and EDCI (1.1 equiv/equiv NH2 group) in CH2Cl2 (10 mL) was stirred at rt for 15 min. Aminocalixarene (1 mmol) was added and the reaction medium was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and this organic phase was washed successively with 1 M HCl aqueous, saturated NaHCO3 aqueous, water, and brine. The organic phase was dried over Na2SO4 then evaporated by rotary evaporation. The crude product was purified by chromatography.4.4.1. 25,27-Bis-(1-(2-(2-[4-(3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl)phenyl]carbamoyl ethoxy)ethoxy))-26,28-bis-(1-(3-cyanopropoxy))calix[4]arene, 1,3-alternate 15Chromatography (CH2Cl2/MeOH 98:2). Yield 81%; beige solid; mp=162-168 C; IR (ATR) vmax cm-1: 3259, 2920, 2873, 1647, 1621, 1610, 1586; 1H NMR (CDCl3, 500 MHz) delta 1.66 (br q, 4H), 1.97 (t, J=7.3 Hz, 4H), 3.23 (t, J=5.3 Hz, 4H), 3.35-3.45 (m, 6H), 3.50-3.70 (m, 10H), 3.77 (d, J=16.3 Hz, 4H), 3.85 (d, J=16.4 Hz, 4H), 6.62 (t, J=7.3 Hz, 2H), 6.79 (t, J=7.5 Hz, 2H), 6.87 (m, 18H), 7.23-7.37 (m, 6H), 7.52 (d, J=8.4 Hz, 4H), 7.97 (d, J=8.4 Hz, 4H), 8.06 (d, J=8.0 Hz, 2H), 9.66 (s, 2H); 13C NMR (CDCl3, 125 MHz) delta 13.45, 25.68, 37.95, 40.30, 67.58, 69.37, 69.48, 69.61, 110.33, 113.20, 117.13, 118.31, 119.11, 119.81, 119.94, 122.66, 122.82, 125.98, 127.61, 127.84, 128.82, 129.58, 129.72, 131.84, 133.01, 133.78, 134.02, 135.72, 140.53, 152.08, 156.34, 156.47, 157.84, 159.64, 166.41. ESI+-MS: 1466 [MNa]+. ESI+-HRMS [MNa]+: calculated for C86H78N10O12Na: 1465.5698. Found: 1465.5739.4.4.2. 25,27-Bis-(1-(2-(2-[4-(3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl)phenyl]carbamoyl ethoxy)ethoxy))-26,28-bis-(1-(3-cyanopropoxy))calix[4]arene, partial cone 16Chromatography (CH2Cl2/MeOH 98:2). Yield 45%; beige solid; mp=148-149 C; IR (ATR) vmax cm-1: 3295, 3052, 2923, 2864, 1740, 1649, 1621, 1611, 1587; 1H NMR (CDCl3, 500 MHz) delta 1.85-1.90 (m, 2H), 2.05-2.15 (m, 2H), 2.30-2.40 (m, 4H), 3.09 (d, J=13.2 Hz, 2H), 3.44 (br t, 2H), 3.60-3.67 (m, 4H), 3.75-3.95 (m, 16H), 4.02-4.15 (m, 4H), 6.45 (d, J=7.4 Hz, 2H), 6.55 (t, J=7.4 Hz, 2H), 6.66 (t, J=7.5 Hz, 2H), 6.90-6.98 (m, 8H), 7.04-7.09 (m, 6H), 7.15 (d, J=8.2 Hz, 4H), 7.32-7.40 (m, 6H), 7.46 (d, J=8.2 Hz, 4H), 7.91 (d, J=8.2 Hz, 4H), 8.15 (d, J=7.2 Hz, 2H), 9.65 (s, 2H), 11.29 (s, 2H); 13C NMR (CDCl3, 125 MHz) delta 14.14, 14.68, 25.58, 27.19, 30.48, 36.88, 40.68, 69.81, 70.09, 70.81, 72.10, 73.37, 110.42, 113.64, 117.53, 118.80, 119.51, 119.79, 120.38, 121.84, 122.57, 123.00, 123.91, 126.47, 128.07, 128.91, 129.20, 129.42, 129.69, 131.22, 132.27, 132.77, 133.43, 133.97, 134.45, 136.20, 136.66, 140.73, 152.56, 155.15, 156.59, 156.89, 157.47, 158.42, 159.95, 166.57. ESI+-MS: 1466 [MNa]+. ESI+-HRMS [MNa]+: calculated for C86H78N10O12Na: 1465.5698. Found: 1465.5717.

Reference： [1]Tetrahedron,2011,vol. 67,p. 2916 - 2924

28
[ 1300740-31-1 ]
[ 201530-41-8 ]
[ 1300740-34-4 ]

Yield	Reaction Conditions	Operation in experiment
14%		General procedure: A solution of carboxylic acid (1.1 equiv/equiv NH2 group), HOBt (1.1 equiv/equiv NH2 group), and EDCI (1.1 equiv/equiv NH2 group) in CH2Cl2 (10 mL) was stirred at rt for 15 min. Aminocalixarene (1 mmol) was added and the reaction medium was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and this organic phase was washed successively with 1 M HCl aqueous, saturated NaHCO3 aqueous, water, and brine. The organic phase was dried over Na2SO4 then evaporated by rotary evaporation. The crude product was purified by chromatography.

Reference： [1]Tetrahedron,2011,vol. 67,p. 2916 - 2924

29
[ 1300740-32-2 ]
[ 201530-41-8 ]
[ 1300740-35-5 ]

Yield	Reaction Conditions	Operation in experiment
56%		General procedure: A solution of carboxylic acid (1.1 equiv/equiv NH2 group), HOBt (1.1 equiv/equiv NH2 group), and EDCI (1.1 equiv/equiv NH2 group) in CH2Cl2 (10 mL) was stirred at rt for 15 min. Aminocalixarene (1 mmol) was added and the reaction medium was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and this organic phase was washed successively with 1 M HCl aqueous, saturated NaHCO3 aqueous, water, and brine. The organic phase was dried over Na2SO4 then evaporated by rotary evaporation. The crude product was purified by chromatography.

Reference： [1]Tetrahedron,2011,vol. 67,p. 2916 - 2924
[2]Comptes Rendus Chimie,2012,vol. 15,p. 290 - 297

30
[ 1266741-05-2 ]
[ 201530-41-8 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53,p. 610 - 618
[2]Inorganica Chimica Acta,2012,vol. 393,p. 294 - 303

31
[ 1414867-90-5 ]
[ 623-05-2 ]
[ 201530-41-8 ]

Reference： [1]Inorganica Chimica Acta,2012,vol. 393,p. 294 - 303

32
[ 1414867-91-6 ]
[ 623-05-2 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; In water-d2;pH 7.4;Kinetics;	3.4 Hydrogen peroxide triggered conversion of TIP to deferasirox The unmasking reaction of TIP with H2O2 is anticipated to occur as shown in Scheme 2, where oxidation of the boronic acid by H2O2 gives a phenol intermediate that undergoes spontaneous 1,6 elimination to release deferasirox and quinone methide, which converts to 4-hydroxybenzyl alcohol in water [27]. Fig. 8 shows the aromatic region of a 1H NMR spectrum of a 250-muM sample of TIP in D2O after reaction with excess H2O2. The expected products deferasirox and 4-hydroxybenzyl alcohol are clearly identified. The clean conversion of TIP to deferasirox was also observed by LC/MS, as shown by the chromatograms in Fig. 9. The rate of the unmasking reaction was assessed by UV-Vis spectrophotometry. As can be seen in Fig. 10, the UV-Vis spectrum of 20 muM TIP in PBS buffer pH 7.4 changes upon exposure to H2O2. The increase in absorbance at 273 nm versus time for solutions of TIP under pseudo first-order conditions of excess of H2O2 was used to obtain observed rate constants kobs. The second-order rate constant for this reaction was then obtained from the data shown in Fig. 10 to be 1.4 M-1s-1, a value that is similar to that found for prochelator BHAPI, which also contains a self-immolative boronate protecting group [27].

Reference： [1]Inorganica Chimica Acta,2012,vol. 393,p. 294 - 303

33
[ 4510-12-7 ]
[ 201530-41-8 ]

Reference： [1]Inorganica Chimica Acta,2012,vol. 393,p. 294 - 303

34
[ 1218-69-5 ]
[ 201530-41-8 ]

Reference： [1]Inorganica Chimica Acta,2012,vol. 393,p. 294 - 303

35
[ 1972-71-0 ]
[ 619-67-0 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With trifluoroacetic acid; In ethanol; for 4h;Reflux;	Disalicylimide (4) (3.7 g, 14.32 mmol) and 4-hydrazinobenzoic acid (2.6 g, 17.14 mmol) were suspended in ethanol (50 ml) and refluxed, adding TFA in portions until most of the reagents were dissolved ( 6% v/v), monitoring the reaction progress by HPLC. After 4h no more starting material was present. The mixture was cooled and concentrated. After cooling the precipitate was filtered. The solid was recrystallized from ethanol-water, filtered, washed with mixture ethanol-water and dried for 24 h in vacuum to give desired compound with 85% yield..H NMR (400 MHz, DMSO- d6): delta: 6.87 (d, J=8.4 Hz, 1H), 7.045-6.97 (m, 3H), 7.24 (m, 2H), 7.405 (qd, 3=7.6, 1.6 Hz, 2H), 7.558 (d, J=10 Hz, 3H), 7.98 (d, J=8.4 Hz, 2H), 8.059 (dd, 5=7.6, 2 Hz, 1H), 10.059 (s, OH), 10.812 (s, OH). EI-MS calcd for C21H15N304 MW 373.11, found mlz 373.11Anal Calcd for C21Hi5N304 (373.36): C, 67.56; H, 4.05; N, 11.25 Found: C, 67.48; H, 4.0; N, 10.98.

Reference： [1]Patent: WO2011/70560,2011,A1 .Location in patent: Page/Page column 62

36
[ 1311284-26-0 ]
[ 14685-90-6 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
85%		.2 mol of compound II (X = SiMe3) was added to a solution of 4- hydrazinobenzoic acid ethyl ester (0.3 mol) in 150 ml of ethanol abs. The mixture was stirred at room temperature under TLC monitoring. After completion of the reaction, water was added until some perturbation (i.e. a first sign of precipitation) was observed. The mixture was concentrated to a total volume of 50% under reduced pressure and aqueous 6 M HC1 (40 mL) was added. The mixture was stirred until TLC analysis indicated complete deprotection of protecting groups and deferasirox formation. The resulting solid was filtered, washed with mixture ethanol-water and dried for 24 h in vacuum (85% yield). The solid was allowed to stand exposed to the air to form the monohydrate.

Reference： [1]Patent: WO2011/70560,2011,A1 .Location in patent: Page/Page column 61

37
[ 1441-87-8 ]
[ 201530-41-8 ]

Reference： [1]Patent: WO2011/70560,2011,A1
[2]Patent: US2016/24025,2016,A1
[3]Patent: US2016/24025,2016,A1
[4]Angewandte Chemie - International Edition,2019,vol. 58,p. 8773 - 8778
Angew. Chem.,2019,vol. 131,p. 8865 - 8870,6

38
[ 36850-04-1 ]
[ 201530-41-8 ]

Reference： [1]Patent: WO2011/70560,2011,A1

39
iron(III) chloride [ No CAS ]
[ 201530-41-8 ]
FeCl₃*C₂₁H₁₅N₃O₄ [ No CAS ]

Reference： [1]ChemPlusChem,2012,vol. 77,p. 1001 - 1016

40
iron(III) chloride [ No CAS ]
[ 201530-41-8 ]
FeCl₃*2C₂₁H₁₅N₃O₄ [ No CAS ]

Reference： [1]ChemPlusChem,2012,vol. 77,p. 1001 - 1016

41
[ 1452593-26-8 ]
[ 201530-41-8 ]
[ 1452593-23-5 ]

Reference： [1]ChemPlusChem,2012,vol. 77,p. 1001 - 1016

42
[ 1354913-88-4 ]
[ 201530-41-8 ]
[ 1452593-24-6 ]

Reference： [1]ChemPlusChem,2012,vol. 77,p. 1001 - 1016

43
terbium(III) chloride hexahydrate [ No CAS ]
[ 201530-41-8 ]
terbium(III)-deferasirox [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;pH 7.4;	A stock solution (5.0 104 M) of Tb3+-DFX complex was preparedby mixing and gentle stirring of 1 ml of 1.0 103 M terbium(III) solution and 1 ml 1.0 103 M DFX solution. The pH ofall solutions was adjusted with the Tris-HCl buffer solution(0.01 M, pH 7.4).

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2014,vol. 120,p. 467 - 472

44
[ 1453-82-3 ]
[ 201530-41-8 ]
[ 1557019-77-8 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol;	Example 1 To 51 mg isonicotinamide and 150 mg <strong>[201530-41-8]Deferasirox</strong> was added 100 muIota methanol. This mixture was vigorously ground to dryness in an agate mortar. Then another 100 muIota methanol was added and grinding was carried out. Investigation of the solid material by XRPD shows that an new solid form that is still containing some <strong>[201530-41-8]Deferasirox</strong> form A is obtained. The mixture of the multi- component crystalline system with <strong>[201530-41-8]Deferasirox</strong> form A was further processed by addition of 4 ml of acetone. The resulting suspension was shortly heated to reflux temperature and then stirred at r.t in an open vial allowing about 3 ml of the solvent to evaporate before the solid was separated by filtration. Investigation of the resulting crystalline material by XRPD shows a powder pattern as shown in Figure 1 with peak locations as provided in table 2. Further analysis by H- NMR reveals a molar ratio of about 1 :1 of <strong>[201530-41-8]Deferasirox</strong> and Isonicotinamide.

Reference： [1]Patent: WO2014/23682,2014,A1 .Location in patent: Page/Page column 10
[2]RSC Advances,2017,vol. 7,p. 43151 - 43160

45
[ 1642597-27-0 ]
[ 99768-12-4 ]
[ 201530-41-8 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53,p. 610 - 618

46
[ 1642597-20-3 ]
[ 201530-41-8 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53,p. 610 - 618

47
[ 1642597-21-4 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
1.7g	With 2-(diethylamine)ethanethiol; sodium t-butanolate; In N,N-dimethyl-formamide; at 150℃; for 2h;Inert atmosphere;	To a solution of 2-(diethylamino)ethanethiol (2.7 g,20 mmol) in dimethylformamide (27 mL) under nitrogen atmosphere was added sodium tert-butoxide(3.0 g, 0.3 mmol) at 0C. Into the resulting solution, methyl 4-(3,5-bis(2-methoxyphenyl)-1H-1,2,4-triazol-1-yl) benzoate (5, 2.1 g, 5.1 mmol) was added and stirred at 150C for 2 h during which TLC showed the completion of the reaction. It was cooled to 25C followed by the addition of water (150 mL). It was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford Deferasirox (1.7 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 6.87 (d, 1H),7.045-6.97 (m, 3H), 7.24 (m, 2H), 7.405 (qd, Hz, 2H),7.558 (d, 3H), 7.98 (d, 2H), 8.059 (dd, 2 Hz, 1H),10.059 (s, OH), 10.812 (s, OH).

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53,p. 610 - 618

48
[ 106724-85-0 ]
[ 201530-41-8 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53,p. 610 - 618

49
[ 1642597-22-5 ]
[ 201530-41-8 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53,p. 610 - 618

50
[ 67-56-1 ]
[ 7722-84-1 ]
molybdenum(VI) oxide [ No CAS ]
[ 201530-41-8 ]
C₂₂H₁₇MoN₃O₈ [ No CAS ]

Reference： [1]RSC Advances,2015,vol. 5,p. 101076 - 101088

51
[ 67-56-1 ]
[ 7722-84-1 ]
molybdenum(VI) oxide [ No CAS ]
[ 201530-41-8 ]
C₂₁H₁₇MoN₃O₆ [ No CAS ]

Reference： [1]RSC Advances,2015,vol. 5,p. 101076 - 101088

52
[ 67-56-1 ]
bis(acetylacetonato)dioxidomolybdenum(VI) [ No CAS ]
[ 201530-41-8 ]
C₂₂H₁₇MoN₃O₇ [ No CAS ]

Reference： [1]RSC Advances,2015,vol. 5,p. 101076 - 101088

53
2-(2-hydroxyphenyl)benz[e]oxazin-4-one [ No CAS ]
[ 619-67-0 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
310 g	In water; at 90℃; for 2h;	To about 200 g of 2-(2-Hydroxyphenyl)benz[e]oxazin-4-one (Formula-4) in water (3 L), about 150 g of 4-hydrozenobenzoic acid (Formula-5) is added and heated at 90 C. for 2 h. The suspension is cooled to ambient temperature for complete precipitation to obtain the precipitate. Thereafter, the precipitate is filtered and washed with isopropanol (250 ml) twice, and sucked dry to obtain deferasirox (Formula-1) (310 g) having pale yellow colour.

Reference： [1]Patent: US2016/24025,2016,A1 .Location in patent: Paragraph 0082-0083

54
2-(2-Hydroxyphenyl)benz[e]oxazin-4-one sodium salt [ No CAS ]
[ 619-67-0 ]
[ 201530-41-8 ]

Yield	Reaction Conditions	Operation in experiment
125 g		To about 100 g of 2-(2-Hydroxyphenyl)benz[e]oxazin-4-one sodium salt in isopropanol (1.5 L), about 70 g of 4-hydrozenobenzoic acid (Formula-5) is added and refluxed for about 2 h. After completion of the reaction, the reaction mixture is cooled to ambient temperature for complete precipitation. The precipitated solid is isolated by filtration. The obtained solid is washed with isopropanol (100 ml). The resulting solid is suspended in isopropanol and acidified to pH 4 using hydrochloric acid. The reaction mixture is stirred for complete precipitation, to obtain the precipitate having crude Deferasirox. The crude Deferasirox is isolated by filtration of the precipitate and drying the precipitate under vacuum to obtain semi-pure deferasirox (Formula-1) (125 g) having greyish yellow colour.

Reference： [1]Patent: US2016/24025,2016,A1 .Location in patent: Paragraph 0081

55
[ 3153-26-2 ]
[ 201530-41-8 ]
[V(V)O(μ-4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid)(OMe)]₂ [ No CAS ]

Reference： [1]European Journal of Inorganic Chemistry,2016,vol. 2016,p. 1430 - 1441

56
[ 5680-79-5 ]
[ 201530-41-8 ]
methyl 2-(4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzamido)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%		General procedure: A solution of carboxylic acid (1.1 equiv. per equiv. of NH2 group), DCC (1.1 equiv. per equiv. of NH2 group), and DMAP (equiv. per equiv. of NH2 group) in CH2Cl2 (10ml per mmol of aminoacid) was stirred at RT for 15min The methyl ester of aminoacid was added and the reaction was stirred at RT overnight (Rouge et al., 2012). The reaction was diluted with CH2Cl2 (100ml per mmol of aminoacid) and this organic phase was washed successively with 1Maqueous HCl, saturated aqueous NaHCO3, water, andbrine. The organic phase was dried over anhydrous Na2SO4 and then evaporated by rotary evaporation under reduced pressure. The crude product was purified by column chromatography using CHCl3/MeOH (19:1) as eluent and then recrystallized in EtOH. 2.2.2.1 Methyl2-(4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzamido)-acetate (DFXGly) (0013) This compound was obtained from glycine methyl ester hydrochloride (0.391mmol, 0.20g). A pale red solid, (172mg, Yield=51%). M.p. 190-195;. IR (KBr, cm-1) nu 3248, 2929, 2847, 1745 (nuC=O glaycinat), 1670 (nuC=O <strong>[201530-41-8]deferasirox</strong>), 1608, 1589, 1516, 1409, 1352, 1252, 1158, 1068, 989, 857, 757, 690. 1H NMR (DMSO-d6, ppm) delta=3.33 (s, 3H, CH3), 3.66 (s, 2H, CH2), 6.85 (d, 1H), 6.96-7.04 (m, 3H), 7.38 (m, 2H), 7.52 (d, 1H), 7.55 (d, 2H), 8.06 (d, 2H), 8.19 (d, 1H), 9.09 (br s, 1H,-NH), 10.41 (br s, 1H,-OH), 10.76 (br s, 1H,-OH). 13C NMR (DMSO-d6, ppm): delta=42.3 (CH3), 52.4(CH2), 113.6, 114.0, 116.8 (CH), 117.0 (CH), 119.4 (CH), 119.8 (CH), 123.8 (2CH), 127.1 (CH), 130.8 (2CH), 130.9, 131.0 (CH), 131.8 (CH), 132.0, 141.9 (CH), 152.1, 155.6, 156.4, 159.4 (C=O ), 179.3 (C=O glaycinat); MS (m/z) 444 for C24H20N4O5 (444): Anal. Calc. for C24H20N4O5: C 64.86, H 4.54, N 12.61; found C 64.68, H 4.38, N 12.52.

Reference： [1]European Journal of Pharmacology,2016,vol. 781,p. 209 - 217

57
[ 5619-07-8 ]
[ 201530-41-8 ]
methyl 2-(4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzamido)phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		General procedure: A solution of carboxylic acid (1.1 equiv. per equiv. of NH2 group), DCC (1.1 equiv. per equiv. of NH2 group), and DMAP (equiv. per equiv. of NH2 group) in CH2Cl2 (10ml per mmol of aminoacid) was stirred at RT for 15min The methyl ester of aminoacid was added and the reaction was stirred at RT overnight (Rouge et al., 2012). The reaction was diluted with CH2Cl2 (100ml per mmol of aminoacid) and this organic phase was washed successively with 1Maqueous HCl, saturated aqueous NaHCO3, water, andbrine. The organic phase was dried over anhydrous Na2SO4 and then evaporated by rotary evaporation under reduced pressure. The crude product was purified by column chromatography using CHCl3/MeOH (19:1) as eluent and then recrystallized in EtOH.

Reference： [1]European Journal of Pharmacology,2016,vol. 781,p. 209 - 217

58
[ 201530-41-8 ]
C₃₂H₃₇N₅O₇ [ No CAS ]

Reference： [1]Patent: US2016/296629,2016,A1

59
[ 201530-41-8 ]
C₂₇H₂₉N₅O₅ [ No CAS ]

Reference： [1]Patent: US2016/296629,2016,A1

60
[ 64-17-5 ]
[ 201530-41-8 ]
[ 201530-79-2 ]

Reference： [1]Patent: US2016/296629,2016,A1 .Location in patent: Paragraph 0092

61
[ 75-31-0 ]
[ 201530-41-8 ]
C₂₄H₂₂N₄O₃ [ No CAS ]

Reference： [1]Patent: US2016/296629,2016,A1 .Location in patent: Paragraph 0092

62
[ 619-67-0 ]
[ 21958-32-7 ]
[ 201530-41-8 ]

Reference： [1]MedChemComm,2016,vol. 7,p. 2290 - 2298
[2]MedChemComm,2017,vol. 8,p. 1953 - 1964

63
[ 109-85-3 ]
[ 201530-41-8 ]
C₂₄H₂₂N₄O₄ [ No CAS ]

Reference： [1]RSC Advances,2017,vol. 7,p. 11158 - 11169

64
[ 5036-48-6 ]
[ 201530-41-8 ]
C₂₇H₂₆N₆O₃ [ No CAS ]

Reference： [1]RSC Advances,2017,vol. 7,p. 11158 - 11169

65
potassium titanium oxalate dehydrate [ No CAS ]
[ 201530-41-8 ]
Ti(4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazole-1-yl]benzoic acid)₂ [ No CAS ]

Reference： [1]Inorganic Chemistry,2017,vol. 56,p. 7788 - 7802

66
[ 1453-82-3 ]
[ 201530-41-8 ]
C₂₁H₁₅N₃O₄*2C₆H₆N₂O [ No CAS ]

Reference： [1]RSC Advances,2017,vol. 7,p. 43151 - 43160

67
[ 572-09-8 ]
[ 201530-41-8 ]
deferasirox-di-D-galactopyranoside [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; water; at 20℃; for 18h;	To a suspension of <strong>[201530-41-8]deferasirox</strong> (1 6 g, 42 mmol), tetra-butylammonium bromide (5 g, 20 mmol) and 2,3,4,6-tetra-0-acetyl-beta-D-galactopyranosyl bromide (43 g, 100 mmol) in dichloromethane (250 ml) was added water (250 ml) and 10 N sodium hydroxide solution (15 ml) and the reaction mixture was vigorously stirred for 18 hours at room temperature. The pH of the reaction mixture was adjusted to 4.5 with acetic acid, the organic layer was separated and concentrated in vacuum. The residue was purified by flash chromatography [petroleum ether/ ethyl acetate (1 :1 )] affording 2b (29 g, 67 %, 28 mmol) as a white foam. 1H NMR (400 MHz, DMSO-d6) delta ppm 1 .56 (s, 3 H) 1 .86 (s, 3 H) 1 .94 (s, 3H) 1 .96 (s, 3H) 1 .98 (s, 3H), 1 .99 (s, 3H) 2.12 (s, 3 H) 2.14 (s, 3 H) 3.90- 4.09 (m, 4 H) 4.29 (t, J=6.5 Hz, 1 H) 4.50 (t, J=6.4 Hz, 1 H) 4.81 (dd, J=10.4, 8.0 Hz, 1 H) 5.10 (dd, J=10.5, 3.6 Hz, 1 H) 5.20 - 5.26 (m, 2 H) 5.30 -5.35 (m, 2 H) 5.43 (dd, J=10.5, 3.5 Hz, 1 H) 6.12 (d, J=7.9 Hz, 1 H) 6.98 - 7.04 (m, 2 H) 7.1 6 (d, J=8.0 Hz, 1 H) 7.29 (t, J=7.3 Hz, 1 H) 7.34 - 7.40 (m, 1 H) 7.56 (d, J= 8.8 Hz, 2H) 7.61 - 7.65 (m, 1 H) 7.69 (d, J=7.5 Hz, 1 H) 7.97 (d, J=8.0 Hz, 2 H) 8.05 (d, J=8.0 Hz, 1 H) 10.60 (s, 1 H)

Reference： [1]Patent: WO2018/134412,2018,A1 .Location in patent: Paragraph 00133; 00134

68
[ 201530-41-8 ]
deferasirox-beta-D-galactopyranoside methyl ester [ No CAS ]

Reference： [1]Patent: WO2018/134412,2018,A1

69
[ 201530-41-8 ]
deferasirox-beta-D-galactopyranoside [ No CAS ]

Reference： [1]Patent: WO2018/134412,2018,A1

70
[ 201530-41-8 ]
4-(3,5-bis(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazol-1-yl)benzoic acid [ No CAS ]