[ CAS No. 203302-95-8 ] {[proInfo.proName]}

Name: 203302-95-8|4-Bromo-3,5-difluoroaniline|97%
Brand: Ambeed
SKU: A562466
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Quality Control of [ 203302-95-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 203302-95-8 ]

CAS No. :	203302-95-8	MDL No. :	MFCD00236593
Formula :	C₆H₄BrF₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DKKUSFDAHRASGO-UHFFFAOYSA-N
M.W :	208.00	Pubchem ID :	2736260
Synonyms :

Calculated chemistry of [ 203302-95-8 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	38.46
TPSA :	26.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.66
Log Po/w (XLOGP3) :	2.13
Log Po/w (WLOGP) :	3.16
Log Po/w (MLOGP) :	3.1
Log Po/w (SILICOS-IT) :	2.66
Consensus Log Po/w :	2.54

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.92
Solubility :	0.253 mg/ml ; 0.00121 mol/l
Class :	Soluble
Log S (Ali) :	-2.31
Solubility :	1.02 mg/ml ; 0.00492 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.46
Solubility :	0.073 mg/ml ; 0.000351 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.43

Safety of [ 203302-95-8 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P261-P280-P305+P351+P338-P311	UN#:	2811
Hazard Statements:	H302+H312-H315-H319-H331-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 203302-95-8 ]

* 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 [ 203302-95-8 ]
Downstream synthetic route of [ 203302-95-8 ]

[ 203302-95-8 ] Synthesis Path-Upstream 1~3

1
[ 372-39-4 ]
[ 203302-95-8 ]

Yield	Reaction Conditions	Operation in experiment
80.2%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃;	Intermediate H5,7-difluoro-quinoline-6-carbaldehyde 2 ¹ DⁿM^"BF^uLi i ii intermediate H 5,7-difluoro-phenylamine (10.0 g, 77.5 mmol) was dissolved in DMF (100 ml_). NBS (13.9 g, 78.0 mmol) was then added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with Et₂O and washed with brine. The separated organic phase was dried (Na₂SO₄) and concentrated to give an oil which is purified by column chromatography to give 4-bromo-3,5-difluoro-phenylamine (i) (12.9 g, 80.2percent)A mixture of 4-bromo-3,5-difluoro-phenylamine (i) (6.0 g, 28.8 mmole), 1.82 g ferrous sulfate, 8.6 ml. glycerol, 1.79 ml. nitrobenzene , and 5.0 ml. concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for five hours. Nitrobenzene was removed by distillation in vacuo. The aqueous solution was acidified with glacial acetic acid, and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate= 12/1 ) to give 6-bromo-5,7-difluoroquinoline (ii) as a white solid (3.5 g, 49.8percent).To a solution of 6-bromo-5,7-difluoroquinoline (ii) (250 g, 1.02 mol) in anhydrous THF (2200 ml.) at -78⁰C, was added a solution of n-BuLi in hexane ( 2.5 M, 408 ml ,1.02 mol) dropwis. The resulting mixture was stirred for additional 30 min at -78⁰C. Then, a solution of DMF (79 ml_, 1.02 mol) in anhydrous THF (200 ml.) was added while the temperature was kept lower than -70⁰C, and the mixture was stirred at the same temperature for 30 mins. The reaction mixture was warmed slowly to room temperature and diluted with aqueous saturated solution of NH₄CI (1000 ml.) and water (800 ml_). The mixture was extracted with ethyl acetate twice, the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give brown oil, which was purified by column chromatography on silica gel eluted with petroleum and ethyl acetate (10:1 ) to give 5,7-difluoro-quinoline-6- carbaldehyde (intemediate H) as a yellow soild (100 g, 50percent). ¹H NMR (DMSO, 300MH) δ(ppm): 10.38(s, 1 H), 9.10~9.12(m, 1 H), 8.62~8.66(m,1 H),7.68~7.78(m,2H)
148 g	With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 2.16667 h;	To a solution of commercial 3,5-difluoronaniline (100 g, 770 mmoles) in DMF (310 mL) there is added a solution of N-bromosuccinimide (140 g, 786 mmoles) in DMF (310 mL) in the course of 40 minutes. The resulting solution is stirred at ambient temperature for 1½ hours. The whole is transferred to 8 L of water, which causes the desired intermediate to precipitate. The solid is filtered over a frit and then rinsed with copious amounts of water. The solid obtained is dried in the air for 48 hours: 148 g of the expected intermediate in the form of a white solid are obtained and used without additional treatment in the following step. ¹H NMR (400 MHz, DMSO-d₆): δ 6.3 (2d, 2H), 3.90 (m, 2H) IR (cm^-1): 3479-3392;

Reference： [1] Patent: WO2011/18454, 2011, A1, . Location in patent: Page/Page column 59-60
[2] Patent: WO2004/48314, 2004, A1, . Location in patent: Page 31-32
[3] Patent: US2017/137385, 2017, A1, . Location in patent: Paragraph 0243; 0244; 0245; 0246

2
[ 541539-64-4 ]
[ 203302-95-8 ]

Reference： [1] Tetrahedron Letters, 2009, vol. 50, # 37, p. 5245 - 5247

3
[ 203302-95-8 ]
[ 123688-59-5 ]

Reference： [1] Patent: US2017/137385, 2017, A1,

[ 203302-95-8 ] Synthesis Path-Downstream 1~88

1
[ 372-39-4 ]
[ 203302-95-8 ]

Yield	Reaction Conditions	Operation in experiment
80.2%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;	Intermediate H5,7-difluoro-quinoline-6-carbaldehyde 2 1 DnM"BFuLi i ii intermediate H 5,7-difluoro-phenylamine (10.0 g, 77.5 mmol) was dissolved in DMF (100 ml_). NBS (13.9 g, 78.0 mmol) was then added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with Et2O and washed with brine. The separated organic phase was dried (Na2SO4) and concentrated to give an oil which is purified by column chromatography to give 4-bromo-3,5-difluoro-phenylamine (i) (12.9 g, 80.2%)A mixture of 4-bromo-3,5-difluoro-phenylamine (i) (6.0 g, 28.8 mmole), 1.82 g ferrous sulfate, 8.6 ml. glycerol, 1.79 ml. nitrobenzene , and 5.0 ml. concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for five hours. Nitrobenzene was removed by distillation in vacuo. The aqueous solution was acidified with glacial acetic acid, and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate= 12/1 ) to give 6-bromo-5,7-difluoroquinoline (ii) as a white solid (3.5 g, 49.8%).To a solution of 6-bromo-5,7-difluoroquinoline (ii) (250 g, 1.02 mol) in anhydrous THF (2200 ml.) at -780C, was added a solution of n-BuLi in hexane ( 2.5 M, 408 ml ,1.02 mol) dropwis. The resulting mixture was stirred for additional 30 min at -780C. Then, a solution of DMF (79 ml_, 1.02 mol) in anhydrous THF (200 ml.) was added while the temperature was kept lower than -700C, and the mixture was stirred at the same temperature for 30 mins. The reaction mixture was warmed slowly to room temperature and diluted with aqueous saturated solution of NH4CI (1000 ml.) and water (800 ml_). The mixture was extracted with ethyl acetate twice, the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give brown oil, which was purified by column chromatography on silica gel eluted with petroleum and ethyl acetate (10:1 ) to give 5,7-difluoro-quinoline-6- carbaldehyde (intemediate H) as a yellow soild (100 g, 50%). 1H NMR (DMSO, 300MH) delta(ppm): 10.38(s, 1 H), 9.10~9.12(m, 1 H), 8.62~8.66(m,1 H),7.68~7.78(m,2H)
	With N-Bromosuccinimide; In DMF (N,N-dimethyl-formamide); at 20℃;	L 4-Cyclopropyl-3, 5-difluoro-2-chloroaniline 3, 5-Difluoroaniline (10.0 g, 77.5 MMOL) is dissolved in DMF (100 mL). NBS (13.9 g, 78.0 MMOL) is added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture is diluted with ET20 and washed with brine. The separated organic phase is dried (NA2SO4) and concentrated to give an oil which is purified by column chromatography (METHYLENE CHLORIDE/HEXANES) to give 4-bromo-3, 5-difluoroaniline. 4-Bromo-3, 5-difluoroaniline (10.5 g, 50.5 MMOL) is dissolved in DMF (100 mL). NCS (28.6 g, 50.5 MMOL) is added portionwise at room temperature. After 48 hours, the reaction is diluted with ET20 and washed with brine. The separated organic phase is dried (NA2SO4) and concentrated to give an oil. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-bromo-2-chloro-3, 5-difluoroaniline. A mixture of 4-bromo-2-chloro-3, 5-difluoroaniline (5.35 g, 22.0 MMOL), cyclopropylboronic acid (2.20 g, 24.0 MMOL), K3P04 (16 g, 78 MMOL) and tricyclohexyl phosphine (0.623 g, 2.24 MMOL) in toluene (30 mL) and water (8 mL) is degassed with N2 and heated to 100C. Pd (OAC) 2 (0.25 g, 1.16 MMOL) is added. The reaction mixture is heated to 100C overnight, cooled and loaded directly on a column of silica gel. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-cyclopropyl-3, 5-difluoro-2- chloroaniline.
148 g	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2.16667h;	To a solution of commercial 3,5-difluoronaniline (100 g, 770 mmoles) in DMF (310 mL) there is added a solution of N-bromosuccinimide (140 g, 786 mmoles) in DMF (310 mL) in the course of 40 minutes. The resulting solution is stirred at ambient temperature for 1½ hours. The whole is transferred to 8 L of water, which causes the desired intermediate to precipitate. The solid is filtered over a frit and then rinsed with copious amounts of water. The solid obtained is dried in the air for 48 hours: 148 g of the expected intermediate in the form of a white solid are obtained and used without additional treatment in the following step. 1H NMR (400 MHz, DMSO-d6): delta 6.3 (2d, 2H), 3.90 (m, 2H) IR (cm-1): 3479-3392;

Reference： [1]Patent: WO2011/18454,2011,A1 .Location in patent: Page/Page column 59-60
[2]Patent: WO2004/48314,2004,A1 .Location in patent: Page 31-32
[3]Patent: US2017/137385,2017,A1 .Location in patent: Paragraph 0243; 0244; 0245; 0246

2
[ 203302-95-8 ]
[ 702644-83-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-chloro-succinimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h;	L 4-Cyclopropyl-3, 5-difluoro-2-chloroaniline 3, 5-Difluoroaniline (10.0 g, 77.5 MMOL) is dissolved in DMF (100 mL). NBS (13.9 g, 78.0 MMOL) is added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture is diluted with ET20 and washed with brine. The separated organic phase is dried (NA2SO4) and concentrated to give an oil which is purified by column chromatography (METHYLENE CHLORIDE/HEXANES) to give 4-bromo-3, 5-difluoroaniline. 4-Bromo-3, 5-difluoroaniline (10.5 g, 50.5 MMOL) is dissolved in DMF (100 mL). NCS (28.6 g, 50.5 MMOL) is added portionwise at room temperature. After 48 hours, the reaction is diluted with ET20 and washed with brine. The separated organic phase is dried (NA2SO4) and concentrated to give an oil. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-bromo-2-chloro-3, 5-difluoroaniline. A mixture of 4-bromo-2-chloro-3, 5-difluoroaniline (5.35 g, 22.0 MMOL), cyclopropylboronic acid (2.20 g, 24.0 MMOL), K3P04 (16 g, 78 MMOL) and tricyclohexyl phosphine (0.623 g, 2.24 MMOL) in toluene (30 mL) and water (8 mL) is degassed with N2 and heated to 100C. Pd (OAC) 2 (0.25 g, 1.16 MMOL) is added. The reaction mixture is heated to 100C overnight, cooled and loaded directly on a column of silica gel. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-cyclopropyl-3, 5-difluoro-2- chloroaniline.
	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 60℃; for 1.5h;	mixture of <strong>[203302-95-8]4-bromo-3,5-difluroaniline</strong> (400 mg, 1.923 mmol) and NCS (257 mg, 1.923 mmol) in DMF (3.8 mL) was stirred at 60C for 90 min. It was diluted with diethyl ether (40 mL), washed with water (20 mL), and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (eluting with EtOAc/hexane = 50%) to give the title compound. MS (ES+) m/z: 242, 244 (M+H).

Reference： [1]Patent: WO2004/48314,2004,A1 .Location in patent: Page 31-32
[2]Patent: WO2017/74832,2017,A1 .Location in patent: Page/Page column 159-160

3
[ 860617-71-6 ]
[ 203302-95-8 ]
5-(4-amino-2,6-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In tetrahydrofuran; hexane;	A mixture of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (0.782 g, 3.78 mmol), tris(dibenzylidene-acetone)dipalladium (0.096 g, 0.105 mmol), N-methyl-5-cyanopyrroleboronic acid (1.12 g, 7.46 mmol), and potassium fluoride (0.789 g, 13.6 mmol) in THF (10 mL) was stirred under nitrogen. Tri-tert-butylphosphine (10% solution in hexane, 0.621 mL, 0.210 mmol) was added to the mixture and allowed to stir until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/tetrahydrofuran, filtered through a plug of silica gel, the solvent evaporated and the residue purified by silica gel column chromatography (hexane/ethylacetate, 70/30) to afford the title compound (1.77 g, 92%). HPLC purity component=100% at 210-370 mm; RT=8.8 min.; 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra RP18 instrument, 3.5mu, 150×4.6 mm, 1.2 mL/min. HRMS: calcd for C12H9F2N3+H+, 233.0764; found (ESI-FTMS, [M+H]1+), 234.0433.
92%	With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In tetrahydrofuran; hexane;	Example 78 5-(4-amino-2,6-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile A mixture of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (0.782 g, 3.78 mmol), tris(dibenzylidene-acetone)dipalladium (0.096 g, 0.105 mmol), N-methyl-5-cyanopyrroleboronic acid (1.12 g, 7.46 mmol), and potassium fluoride (0.789 g, 13.6 mmol) in THF (10 mL) was stirred under nitrogen. Tri-tert-butylphosphine (10% solution in hexane, 0.621 mL, 0.210 mmol) was added to the mixture and allowed to stir until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/tetrahydrofuran, filtered through a plug of silica gel, the solvent evaporated and the residue purified by silica gel column chromatography (hexane/ethylacetate, 70/30) to afford the title compound (1.77 g, 92%). HPLC purity component=100% at 210-370 nm; RT=8.8 min.; 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra RP18 instrument, 3.5mu, 150*4.6 mm, 1.2 mL/min. HRMS: calcd for C12H9F2N3+H+, 233.0764; found (ESI-FTMS, [M+H]1+), 234.0433

Reference： [1]Patent: US2007/27126,2007,A1 .Location in patent: Page/Page column 17
[2]Patent: US2007/27201,2007,A1 .Location in patent: Page/Page column 24
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7119 - 7122

4
[ 203302-95-8 ]
[ 56-81-5 ]
[ 1022091-49-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sulfuric acid; sodium 3-nitrobenzenesulfonate; In water; at 120 - 130℃; for 1.5h;	The raw materials 3,5-difluoroaniline G-1 (5.6 g, 27 mmol) and sodium 3-nitrobenzenesulfonate (7.2 g, 32 mmol) Was added to a mixed solution of concentrated sulfuric acid (15 mL) and water (6 mL) After heating to an internal temperature of 120 C, glycerol (7.4 g, 80 mmol) After the addition was completed, the temperature was raised to 130 C and reacted for 1.5h, then cooled. The reaction was poured into crushed ice, concentrated ammonia water to adjust the pH to 5 ~ 6, the precipitated solid was filtered off, washed with water, After drying, column chromatography gave 3.82 g of white solid compound G-2 in 58% yield.
49.8%	With sulfuric acid; iron(II) sulfate; In nitrobenzene; for 5h;Heating / reflux;	A mixture of 4-bromo-3,5-difluoro-phenylamine (6.0 g, 28.8 mmol), ferrous sulfate (1.82 g), glycerol (8.6 mL), nitrobenzene (1.79 mL) and 5.0 ml of concentrated sulfuric acid (5 mL) was heated gently. After the first vigorous reaction, the mixture was heated to reflux for five hours. Nitrobenzene was removed by distillation in vacuo. The aqueous solution was acidified with glacial acetic acid, and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum:ethyl acetate= 12:1) to return title compound as a white solid (3.5 g, 49.8%).
49.8%	With sulfuric acid; iron(II) sulfate; In nitrobenzene; for 5h;Reflux;	Intermediate H5,7-difluoro-quinoline-6-carbaldehyde 2 1 DnM"BFuLi i ii intermediate H 5,7-difluoro-phenylamine (10.0 g, 77.5 mmol) was dissolved in DMF (100 ml_). NBS (13.9 g, 78.0 mmol) was then added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with Et2O and washed with brine. The separated organic phase was dried (Na2SO4) and concentrated to give an oil which is purified by column chromatography to give 4-bromo-3,5-difluoro-phenylamine (i) (12.9 g, 80.2%)A mixture of 4-bromo-3,5-difluoro-phenylamine (i) (6.0 g, 28.8 mmole), 1.82 g ferrous sulfate, 8.6 ml. glycerol, 1.79 ml. nitrobenzene , and 5.0 ml. concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for five hours. Nitrobenzene was removed by distillation in vacuo. The aqueous solution was acidified with glacial acetic acid, and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate= 12/1 ) to give 6-bromo-5,7-difluoroquinoline (ii) as a white solid (3.5 g, 49.8%).To a solution of 6-bromo-5,7-difluoroquinoline (ii) (250 g, 1.02 mol) in anhydrous THF (2200 ml.) at -780C, was added a solution of n-BuLi in hexane ( 2.5 M, 408 ml ,1.02 mol) dropwis. The resulting mixture was stirred for additional 30 min at -780C. Then, a solution of DMF (79 ml_, 1.02 mol) in anhydrous THF (200 ml.) was added while the temperature was kept lower than -700C, and the mixture was stirred at the same temperature for 30 mins. The reaction mixture was warmed slowly to room temperature and diluted with aqueous saturated solution of NH4CI (1000 ml.) and water (800 ml_). The mixture was extracted with ethyl acetate twice, the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give brown oil, which was purified by column chromatography on silica gel eluted with petroleum and ethyl acetate (10:1 ) to give 5,7-difluoro-quinoline-6- carbaldehyde (intemediate H) as a yellow soild (100 g, 50%). 1H NMR (DMSO, 300MH) delta(ppm): 10.38(s, 1 H), 9.10~9.12(m, 1 H), 8.62~8.66(m,1 H),7.68~7.78(m,2H)

Reference： [1]Patent: CN105968115,2016,A .Location in patent: Paragraph 0490-0492
[2]Patent: WO2008/144767,2008,A1 .Location in patent: Page/Page column 108
[3]Patent: WO2011/18454,2011,A1 .Location in patent: Page/Page column 59-60
[4]European Journal of Medicinal Chemistry,2017,vol. 134,p. 147 - 158

5
[ 203302-95-8 ]
[ 115822-57-6 ]
C₁₆H₁₂BrF₂NO₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6406 - 6409
[2],2020,vol. 11,p. 583 - 590

6
[ 203302-95-8 ]
[ 102-92-1 ]
4-bromo-3,5-difluoroanilide of cinnamic acid [ No CAS ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 5245 - 5247

7
[ 541539-64-4 ]
[ 203302-95-8 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 5245 - 5247

8
[ 203302-95-8 ]
[ 814-68-6 ]
[ 1202698-01-8 ]

Reference： [1]Journal of Chemical and Engineering Data,2010,vol. 55,p. 1434 - 1436

9
[ 203302-95-8 ]
[ 1185767-02-5 ]

Reference： [1]Patent: WO2011/18454,2011,A1
[2]Patent: CN105968115,2016,A

10
[ 108-31-6 ]
[ 203302-95-8 ]
C₁₀H₆BrF₂NO₃ [ No CAS ]

Reference： [1]Journal of Chemical and Engineering Data,2011,vol. 56,p. 158 - 160

11
[ 108-31-6 ]
[ 203302-95-8 ]
[ 1261159-74-3 ]

Reference： [1]Journal of Chemical and Engineering Data,2011,vol. 56,p. 358 - 360

12
[ 203302-95-8 ]
[ 65352-94-5 ]
[ 163765-44-4 ]
[ 1374891-90-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With N-ethyl-N,N-diisopropylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; dimethyl sulfoxide;	Preparation 31 (R)-4-[5-(4-Bromo-3,5-difluoro-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester To a solution of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (250 mg, 1.2 mmol) dissolved in DCM (5 mL) was added a solution of 2-fluoropyridine-5-carbonyl chloride (190 mg, 1.2 mmol) dissolved in DCM (2 mL) followed by addition of N,N-diisopropylethylamine (100 uL, 0.60 mmol). The reaction mixture was stirred at RT for 1 h, and concentrated to produce a clear oil. The oil from the previous step was dissolved in DMSO (2.6 mL, 36 mmol) and (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (240 mg, 1.2 mmol) and N,N-diisopropylethylamine (2.1 mL, 12 mmol) was added. The reaction mixture was heated at 120 C. overnight and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-40% ethyl acetate:hexanes) to produce the title product as a white solid (yield 62%). (m/z): [M+H]+ calcd for C22H25BrF2N4O3 511.11. 513.11 found 513.4.

Reference： [1]Patent: US2012/114600,2012,A1

13
[ 203302-95-8 ]
[ 321-14-2 ]
[ 1417658-25-3 ]

Yield	Reaction Conditions	Operation in experiment
32%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

14
[ 203302-95-8 ]
[ 344591-91-9 ]
[ 1431386-74-1 ]

Yield	Reaction Conditions	Operation in experiment
22.3%	With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; acetonitrile; at 80℃; for 4h;Inert atmosphere;	A mixture of 4-bromo-2,5-difluoroaniline 32 (312 mg, 1.5 mmol), boronic acid 2 (388 mg, 2 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (70 mg, 10%mol) and K3PO4 (424 mg, 2 mmol) in 2 mL ACN, 2 mL dioxane, and 1 mL H20 was bubbled with argon before heating at 80C for 4h. After cooling down to room temperature, the reaction mixture was taken up in EA, washed with aq. NaHCOs and brine. The organic phase was dried over Na2S04, concentrated and then subjected to silica gel flash columnchromatography (0-80%B, A: hexane; B: EA) to give 3,5-difluoro-4-[l-methyl-3- (trifluoromethyl)pyrazol-5-yl]phenylamine 33 (92.7 mg, purity >95%, yield: 22.3%) as a light brown solid

Reference： [1]Patent: WO2013/59666,2013,A1 .Location in patent: Paragraph 00558

15
[ 203302-95-8 ]
[ 344591-91-9 ]
[ 1431386-10-5 ]

Reference： [1]Patent: WO2013/59666,2013,A1

16
[ 203302-95-8 ]
[ 1467060-36-1 ]

Yield	Reaction Conditions	Operation in experiment
7.34 g	With N-iodo-succinimide; acetic acid; at 20℃; for 2h;	To a solution of the <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (5 g, 20 mmol) in acetic acid (60 mL) was added NIS (5.68 g). The reaction mixture was stirred at room temperature for two hours, and poured into water (300 mL). The product was extracted with ethyl acetate (2*200 mL), and the combined organic layers were washed with 1 N aqueous NaOH (200 mL) and saturated aqueous sodium thiosulfate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The oily residue was filtered through a plug of silica gel, eluting with heptane/ethyl acetate (4:1). The filtrate was concentrated in vacuo to give the title compound (7.34 g) as a white solid. 1H NMR (500 MHz, CDCl3) delta 6.44 (dd, J=10.00, 1.95 Hz, 1H) 4.46 (br. s., 2H).

Reference： [1]Organic Process Research and Development,2018,vol. 22,p. 681 - 696
[2]Patent: US2013/267493,2013,A1 .Location in patent: Paragraph 0809

17
[ 203302-95-8 ]
[ 1467060-37-2 ]

Reference： [1]Patent: US2013/267493,2013,A1
[2]Organic Process Research and Development,2018,vol. 22,p. 681 - 696

18
[ 203302-95-8 ]
[ 1467060-39-4 ]

Reference： [1]Patent: US2013/267493,2013,A1

19
[ 203302-95-8 ]
[ 1467057-66-4 ]

Reference： [1]Patent: US2013/267493,2013,A1

20
[ 203302-95-8 ]
[ 1467060-43-0 ]

Reference： [1]Patent: US2013/267493,2013,A1

21
[ 203302-95-8 ]
[ 1467057-69-7 ]

Reference： [1]Patent: US2013/267493,2013,A1

22
[ 203302-95-8 ]
[ 1467060-46-3 ]

Reference： [1]Patent: US2013/267493,2013,A1

23
[ 203302-95-8 ]
[ 1467057-76-6 ]

Reference： [1]Patent: US2013/267493,2013,A1

24
[ 203302-95-8 ]
[ 1467060-50-9 ]

Reference： [1]Patent: US2013/267493,2013,A1

25
[ 203302-95-8 ]
[ 1467057-80-2 ]

Reference： [1]Patent: US2013/267493,2013,A1

26
[ 203302-95-8 ]
[ 1467060-53-2 ]

Reference： [1]Patent: US2013/267493,2013,A1

27
[ 203302-95-8 ]
[ 1467057-85-7 ]

Reference： [1]Patent: US2013/267493,2013,A1

28
[ 203302-95-8 ]
[ 1154742-51-4 ]

Reference： [1]Patent: US2013/267493,2013,A1
[2]Organic Process Research and Development,2018,vol. 22,p. 681 - 696

29
[ 203302-95-8 ]
[ 1467059-98-8 ]

Reference： [1]Patent: US2013/267493,2013,A1
[2]Organic Process Research and Development,2018,vol. 22,p. 681 - 696

30
[ 203302-95-8 ]
[ 463-71-8 ]
[ 1000577-92-3 ]

Yield	Reaction Conditions	Operation in experiment
5.18 g	With calcium carbonate; In dichloromethane; water; at 0 - 20℃; under 760.051 Torr;Inert atmosphere;	<strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (5 g, 24.0 mmol, Eq: 1.00) and calcium carbonate (5.05 g, 1.72 ml, 50.5 mmol, Eq: 2.1) were suspended in a 50% aqueous dichlormethane (24ml) mixture. The thick suspension was stirred vigorously at 0C. Thiophosgene (3.04 g, 2.03 ml, 26.4 mmol, Eq: 1.1) was added slowly dropwise to the mixture. After the addition the mixture was stirred at 0C for lhr, then stirred overnight at room temperature. The precipitate was filtered and the filter cake was washed with dichloromethane. The phases were separated and the aqueous was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to afford 5.18 g (86%) of the desired product as an off-white solid which was used without further purification.

Reference： [1]Patent: WO2014/6066,2014,A1 .Location in patent: Paragraph 0283

31
[ 203302-95-8 ]
[ 1533434-99-9 ]

Reference： [1]Patent: WO2014/6066,2014,A1

32
[ 203302-95-8 ]
[ 1533424-32-6 ]

Reference： [1]Patent: WO2014/6066,2014,A1

33
[ 203302-95-8 ]
[ 1533424-54-2 ]

Reference： [1]Patent: WO2014/6066,2014,A1

34
[ 203302-95-8 ]
[ 321745-86-2 ]
[ 1616596-28-1 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); XPhos; In tetrahydrofuran; at 60℃;Inert atmosphere;	Step A: tert-butvl (4-amino-2,6-difluorophenyl)acetate: To a solution of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (400 mg, 1.92 mmol) in THF (8 mL) were added Pd2(dba)3 (141 mg, 0.154 mmol), X-Phos (110 mg, 0.23 1 mmol). The reaction mixture was degassed and filled withnitrogen, followed by addition of 2-(tert-butoxy)-2-oxoethyzink chloride (9.62 mL, 4.81 mmol).The reaction mixture was heated at 60 C overnight, cooled to RT, quenched with sat NH4C1, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, andconcentrated. The residue was purified with preparative TLC (1500 uM, hex/EA=3/ 1) to give title compound. LC/MS [(M+1)] = 244.20, [(M+1-S6)] = 188.21.

Reference： [1]Patent: WO2014/99633,2014,A2 .Location in patent: Page/Page column 98; 99

35
[ 203302-95-8 ]
[ 1616596-29-2 ]

Reference： [1]Patent: WO2014/99633,2014,A2

36
[ 203302-95-8 ]
[ 1616596-27-0 ]

Reference： [1]Patent: WO2014/99633,2014,A2

37
[ 203302-95-8 ]
[ 19398-47-1 ]
C₁₀H₁₀BrF₂NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.9%	With N-ethyl-N,N-diisopropylamine; potassium iodide; In toluene; at 90℃; for 18h;	Step 1 (ML-S1):Potassium iodide (4.7 g, 28.8 mmol), N,N-diisopropylethylamine (3.7 g, 28.8 mmol) and 1 ,4-dibromo-2-butanol (6.6 g, 28.8 mmol) were added successively to the stirred solution of 4-bromo-2,6-difluoroaniline (3 g, 14.4 mmol) in toluene (30 mL) and the mixture was stirred at 90C for 18 h. The reaction mass was filtered, washed with ethyl acetate and the filtrate was washed successively with water, brine; dried over anhydrous sodium sulfate and evaporated in vacuum to give crude the compound intermediate. Purification by column chromatographyover silica gel and using 20% ethyl acetate in pet ether as the eluent afforded 2 g (49.9%) of ML-S1 as a brown solid.

Reference： [1]Patent: WO2014/140279,2014,A1 .Location in patent: Page/Page column 75; 143

38
[ 203302-95-8 ]
C₁₁H₁₀F₂N₂O [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

39
[ 203302-95-8 ]
C₁₁H₈F₂N₂O [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

40
[ 203302-95-8 ]
C₁₁H₈F₄N₂ [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

41
[ 203302-95-8 ]
C₁₁H₉F₄NO [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

42
[ 203302-95-8 ]
C₁₂H₁₁F₄N [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

43
[ 203302-95-8 ]
C₁₇H₂₂F₄N₂O₃ [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

44
[ 203302-95-8 ]
C₁₃H₁₂F₄N₂O₂ [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

45
[ 203302-95-8 ]
C₁₉H₁₈F₄N₄O₂ [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

46
[ 203302-95-8 ]
[ 65352-94-5 ]
[ 1374891-90-3 ]

Reference： [1]Patent: EP2635571,2015,B1

47
[ 203302-95-8 ]
[ 1623-95-6 ]
N-(4-bromo-3,5-difluorophenyl)-4-phenoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With triethylamine; In dichloromethane; at 20℃; for 2h;	To a solution of cyclopropylamine (33 muL, 0.47 mmol) was added Et3N (200 muL, 1.41 mmol), followed by dropwise addition of acid chloride in anhydrous CH2Cl2. The solution was stirred for 2 h at room temperature, then it was washed successively with 10 % HCl, 5 % NaOH, water and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford compounds 7a (85 %) as a white solid.

Reference： [1]Archives of Pharmacal Research,2015,vol. 38,p. 1761 - 1773

48
[ 203302-95-8 ]
[ 65352-94-5 ]
C₁₂H₆BrF₃N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	To a solution of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (250 mg, 1.2 mmol) dissolved in DCM (5 mL) was added a solution of 2-fluoropyridine-5-carbonyl chloride (190 mg, 1.2 mmol) dissolved in DCM (2 mL) followed by addition of N,N-diisopropylethylamine (100 uL, 0.60 mmol). The reaction mixture was stirred at RT for 1 h, and concentrated to produce a clear oil.

Reference： [1]Patent: EP2635571,2015,B1 .Location in patent: Paragraph 0188

49
[ 203302-95-8 ]
[ 2033-24-1 ]
3-((4-bromo-3,5-difluorophenyl)amino)-3-oxopropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	In toluene; at 90℃; for 3h;	First Step A solution of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (2.00 g, 9.62 mmol) and Meldrum's acid (2.77 g, 19.2 mmol) in toluene (18 mL) was stirred at 90 C. for 3 hours. After the reaction mixture was cooled to 0 C., the deposit was collected by filtration. The obtained solid was purified by reverse-phase column chromatography (0.1% formic acid water/acetonitrile) to obtain 3-((4-bromo-3,5-difluorophenyl)amino)-3-oxopropanoate (2.00 g, 71%) as white powder. LCMS: m/z 294[M+H]+

Reference： [1]Patent: US2016/2251,2016,A1 .Location in patent: Paragraph 1690-1692

50
[ 203302-95-8 ]
[ 73183-34-3 ]
3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a mixture of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.75 g, 10.8 mmol), potassium acetate (2.1 g, 21.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.785 g, 0.962 mmol) under nitrogen was added a solution of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (1.5 g, 7.21 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100 C. overnight. After cooling to room temperature, the mixture was diluted with DCM and filtered through Celite. The filtrated was concentrated in vacuo. The residue was purified by Biotage Isolera (1.4 g, 76%). LCMS calculated for C12H17BF2NO2 (M+H)\| m/z=256.1; found 256.2.
59%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a mixture of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (3.30 g, 15.9 mmol), dppf-PdCl2 (0.648 g, 0.793 mmol), bis(pinacolato)diboron (6.04 g, 23.8 mmol) and potassium acetate (3.11 g, 31.7 mmol) was added 1,4-dioxane (31.7 ml) and the reaction flask was evacuated, back filled with nitrogen, then stirred at 100 C. overnight. The reaction mixture was then diluted with DCM and filtered through a pad of Celite. The filtrate was concentrated and purified by Biotage Isolera (flash purification system with ethyl acetate/hexanes at a ratio from 0 to 100%) to provide the desired product as a brown solid (2.4 g, 59%). LC-MS calculated for C12H17BF2NO2 [M+H]+ m/z: 256.1, found 256.1.
	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	A mixture of <strong>[203302-95-8]4-bromo-3,5-difluoroaniline</strong> (23.0 g, 110 mmol), 4,4,4',4,,5,5,5',5'- octamethyl-2,2'-bi(l ,3,2-dioxaborolane) (30.9 g, 122 mmol), dppf (3.0 g, 5.5 mmol), Pd(dppf)Cl2(4.5 g, 5.5 mmol) and KOAc (32.0 g, 331 mmol) in dioxane (230 mL) was heated at 80 C under N2atmosphere for 18 h. The reaction mixture was cooled and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (Si02, petroleum ethenEtOAc = 20: 1) to give the title compound as a light yellow solid. NMR (400 MHz, CDC13): delta 6.13-6.11 (m, 2H), 4.04 (br s, 2H), 1.35 (s, 12H).

Reference： [1]Patent: US2018/72720,2018,A1 .Location in patent: Paragraph 0644; 0645; 0646
[2]Patent: US2018/72741,2018,A1 .Location in patent: Paragraph 0711-0712
[3]Patent: WO2015/161011,2015,A1 .Location in patent: Page/Page column 63; 64

51
[ 203302-95-8 ]
3,5-difluoro-4-(6-isopropylpyridazin-3-yl)aniline [ No CAS ]

Reference： [1]Patent: WO2015/161011,2015,A1

52
[ 203302-95-8 ]
(S)-5-(3,5-difluoro-4-(6-isopropylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-methyl-2-oxopyrrolidin-1-yl)methyl)benzoic acid [ No CAS ]

Reference： [1]Patent: WO2015/161011,2015,A1

53
[ 203302-95-8 ]
3-(2,6-difluoro-4-iodophenyl)-6-isopropylpyridazine [ No CAS ]

Reference： [1]Patent: WO2015/161011,2015,A1

54
[ 203302-95-8 ]
(S)-5-(3,5-difluoro-4-(6-isopropylpyridazin-3-yl)phenoxy)-2-fluoro-4-((4-methyl-2-oxopyrrolidin-1-yl)methyl)-N-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2015/161011,2015,A1

55
[ 203302-95-8 ]
[ 3739-94-4 ]
C₁₉H₉Br₂F₄N₃O₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 917 - 921
Angew. Chem.,2016,vol. 128,p. 929 - 933,5

56
[ 203302-95-8 ]
N-[3-chloro-6-(5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl)-5-fluoro-2-nitrophenyl]glycine ethyl ester [ No CAS ]