[ CAS No. 197520-71-1 ] {[proInfo.proName]}

Name: 197520-71-1|2,3,4-Trifluoro-5-nitrobenzoic acid|97%
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Quality Control of [ 197520-71-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 197520-71-1 ]

SDS Specification

Alternatived Products of [ 197520-71-1 ]

Product Details of [ 197520-71-1 ]

CAS No. :	197520-71-1	MDL No. :	MFCD09753762
Formula :	C₇H₂F₃NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BCMIOBTWFPSPJJ-UHFFFAOYSA-N
M.W :	221.09	Pubchem ID :	15871241
Synonyms :

Calculated chemistry of [ 197520-71-1 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	7.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.1
TPSA :	83.12 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) :	-6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.44
Log Po/w (XLOGP3) :	1.58
Log Po/w (WLOGP) :	2.97
Log Po/w (MLOGP) :	1.8
Log Po/w (SILICOS-IT) :	0.45
Consensus Log Po/w :	1.45

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.37
Solubility :	0.943 mg/ml ; 0.00426 mol/l
Class :	Soluble
Log S (Ali) :	-2.94
Solubility :	0.256 mg/ml ; 0.00116 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.0
Solubility :	2.23 mg/ml ; 0.0101 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.04

Safety of [ 197520-71-1 ]

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

Application In Synthesis of [ 197520-71-1 ]

* 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 [ 197520-71-1 ]
Downstream synthetic route of [ 197520-71-1 ]

[ 197520-71-1 ] Synthesis Path-Upstream 1~3

1
[ 61079-72-9 ]
[ 197520-71-1 ]

Yield	Reaction Conditions	Operation in experiment
97.1%	at 90 - 95℃; for 3.5 h;	A stirred solution of 2,3,4-trifluorobenzoic acid (5) (10 g, 56.8 mmol) in concentrated H2SO4 (98percent, 33.0 g) was treated dropwise with the mixture of concentrated HNO3 (65percent, 6.0g) and H2SO4 (98percent, 6.3g) for 3.5 h between 90 and 95 °C. The reaction progress was monitored by TLC (30percent ethylacetate in hexane). After completion of the reaction, the reaction mixture was cooled to room temperature and ice-water (50g) was added. The precipitation was separated by centrifugation and dried between 50 and 55 °C for 8 h. The crude product was purified by column chromatography using 20percent ethylacetate:hexane as eluent. The solvent was removed under reduced pressure to afford a white solid 6 (12.2 g) in 97.1percent yield.
92%	for 2.5 h;	A 3 litre three neck round bottom flask was charged with 125 ml H₂SO₄. Fuming nitric acid was added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) was added in 5 g portions over 90 minutes. The dark brownish yellow solution was stirred for 60 minutes at which time the reaction was complete. The reaction mixture was poured into 1 litre of an ice: water mixture and extracted with diethyl ether (3 x 600 ml). The combined extracts were dried (MgSO₄) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 min after which time it was filtered to give 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-I) detected.
92%	for 2.5 h;	A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3.x.600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-1) detected.

92%	for 2.5 h;	2, 3,4-Trifluoro-5-nitro-benzoic acid 2A 3 liter three neck round bottom flask is charged with 125 ml H2504. Fuming nitricacid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1(25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solutionis stirred for 60 mm at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3 x 600 ml). The combinedorganic extracts are dried (Mg504) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 mm after which time it is filtered togive 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) nilz 220 (M-1) detected.
78%	With sulfuric acid; nitric acid In water	Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; ¹H-NMR (400 MHz; DMSO)δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0, 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95,1 23.30 (d, J_C-F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid In water	Step a Preparation of 5-Nitro-2,3,4-trifluorobenzoic Acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; ¹H-NMR (400 MHz; DMSO) δ14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0, 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95, 123.30 (d, J_C-F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid In water	Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 percent yield; m.p.;¹H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0, 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95, 123.30 (d, J_C-_F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid In water	Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 percent yield; m.p.;¹H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0. 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95, 123.30 (d, J_C-_F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	for 0.75 h;	To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; ¹H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0, 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95, 123.30 (d, J_C-F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ -120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
75%	at 0 - 20℃; for 6 h;	Example 1; Preparation of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid; [00238] Step A; 2,3,4-Trifluoro-5-mtrobenzoic acid; Fuming HNO₃ 90percent (549.0 g,7.84 mol corrected for 90percent wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H₂SO₄ over 18 minutes with stirring. The solution OfHNO₃ was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H₂SO₄ in a second flask with ice- water bath cooling over an hour. When addition was complete, the reaction solution was allowed to warm to room temperature. After 5 hours, the reaction was complete as determined by HPLC and the reaction mixture (brown solution) was poured into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice over 10 minutes. The yellow slurry was cooled to 14 °C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven-dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 ⁰C under high vacuum overnight to yield 1035.9 g (75percent) of 2,3,4-trifluoro-5-nitrobenzoic acid as a yellowish solid. HPLC was 98 apercent (220 nm) and 100percent (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (IH, apparent dt, J 1.9, 7, Ar-H); ¹⁹F NMR (376 EPO <DP n="51"/>MHz, DMSOd₆) δ -153.9, -131.5, -120.9. ¹³C NMR (100 MHz, DMSO-d₆) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F, dd, J 265, 13), 154 (C-F, dd, J 265, 10), 163 (COOH). IR v^/cnf¹ 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
75%	at 0 - 20℃; for 6.3 h;	Fuming HNO₃ 90percent (549.0 g,7.84 mol corrected for 90percent wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H₂SO₄ over 18 minutes with stirring. The solution Of HNO₃ was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H₂SO₄ in a second flask with ice-water bath cooling over an hour. Upon complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was complete by HPLC and the reaction mixture (brown solution) was poured over 10 minutes into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow slurry was cooled to 14 °C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven- dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 ⁰C under high vacuum overnight to yield 1035.9 g (75percent) of compound 2 as a yellowish solid. HPLC was 98 apercent (220 nm) and 100percent (254 nm). ¹H NMR (400 MHz, d₆ DMSO) δ 8.44 (IH, apparent dt, J 1.9, 7, Ar-H). ¹⁹F NMR (376 MHz, d₆ DMSO) δ -153.9, -131.5, -120.9. ¹³C NMR (100 MHz, d₆ DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, 7251, 10), 148 (C-F₅ dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR v_mJcm^A 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
74.3%	at 15 - 25℃; for 6.25 h;	Trifluorobenzoic acid (70 Kg₅ 398 MoI) in sulphuric acid (96 wtpercent; 194 L) and hexamethyldisiloxane (6,5 Kg₅ 40 MoI)₅ at 23 ⁰C, was added a 1:1 mixture of sulphuric acid (96 wtpercent) and nitric acid (98 wtpercent) (total 70.1 Kg)₅ over 75 min. The temperature of the reaction mixture was maintained between 15 and 25 ⁰C during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg)₅ keeping the temperature of the ice micture below 0 °C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0 ⁰C₅ then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L)₅ and the solid was then suspended in water (280 L) and stirred for 2 hours at 0 °C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45 ⁰C for 2 days, to provide 2,3₅4-Trifluoro-5-nitro benzoic acid (69.4 Kg₅ 74.3percent yiled). ¹H NMR (400 MHz₅ d₆ DMSO) δ 8.44 (IH, apparent dt, J 2, 7, Ar-H). ¹⁹F NMR (376 MHz, d₆ DMSO) δ -153.9, -131.5, -120.9. ¹³C NMR (100 MHz₅ d₆ DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F₅ dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR v_mjcm ^l 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
50%	With sulfuric acid; nitric acid In sulfuric acid at 5 - 20℃; for 2 h;	Example 1 5-FLUORO-6-(2-FLUORO-4-IODO-DHENYLAMINO)-3-METHYL-3H-BENZOIMIDAZOLE-5-CARBOXYLIC ACID (2-- OH-ETHOXY)-AMIDE Step A: Preparation of 2. 3. 4-trifluoro-5-nitrobenzoic acid Fuming HNO3 was added dropwise to the cold (5 TO-10° C) conc. H2SO4 (5L) and stirred in a three-necked round bottom flask (20L), maintaining the temperature between 5 to- 10° C. Then was added 2, 3, E-TRIFTUOROBENZOIC acid (1 kg, 5.6 mol) in portions, maintaining the temperature at 5O C and after completion of the addition the reaction mixture was allowed to warm to room temperature, stirred for 2h and (the suspension becomes light yellow solution) then poured into 30 kg of crushed ice. The mixture was extracted with ether (3 X 4.0 L) and the organic extracts were washed with water (2 X 2L), brine (2.0 L), dried over anhydrous MGS04, filtered and evaporated under vacuum. The residue (cream colored solid) obtained is re-crystallized from hot chloroform provided the title compound as a solid (yellow). Yield : 880G (50percent), mp. 128-129 OC

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[3] Patent: US2003/232869, 2003, A1, . Location in patent: Page 9; 16
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[ 197520-71-1 ]

Reference： [1] Patent: US6160171, 2000, A,

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[ 197520-71-1 ]
[ 284030-57-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With ammonia In water at 0 - 20℃; for 2.5 h; Stage #2: With hydrogenchloride In water	Step B: 4-Amino-2,3-difluoro-5-nitro-benzoic acid 3 [0122] Ammonium hydroxide solution (30percent in water) (35 mL, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 mL water at 0° C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 hours, the reaction mixture is cooled to 0° C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 mL) and extracted with diethyl ether (3.x.50 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95percent) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.
95%	Stage #1: With ammonia In water at 0 - 20℃; for 2.5 h; Stage #2: With hydrogenchloride In water	Ammonium hydroxide solution (-30percent in water) (35 ml, 271 mmol) was added to a solution of 2,3,4-trifluoro-5- nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0 ⁰C with stirring. Upon completion of the ammonium hydroxide addition, the reaction mixture was warmed to room temperature with stirring. After 2.5 hours, the reaction mixture was cooled to 0 ⁰C and concentrated HCl was carefully added until pH of reaction mixture was 0. The reaction mixture was diluted <n="20"/>with water (30 ml) and extracted with diethyl ether (3 x 50 ml). The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure to give 14 g (95percent) of pure desired product: MS APCI (-) m/z 217 (M-I) detected.
95%	Stage #1: With ammonium hydroxide In water at 0 - 20℃; for 2.5 h; Stage #2: With hydrogenchloride In water at 0℃;	Ammonium hydroxide solution (30percent in water) (35 ml, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 ml water at 0° C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0° C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3.x.50 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95percent) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.

95%	With ammonium hydroxide In water at 0 - 20℃; for 2.5 h;	4-Amino-2, 3-difluoro-5-nitro-benzoic acid 3Ammonium hydroxide solution (—30percent in water) (35 ml, 271 mmol) is added to asolution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 ml water at 0 °C with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 °C andconcentrated HC1 is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3 x 50 ml). combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95percent) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.
88%	Stage #1: With ammonia In water at 6 - 20℃; for 5 - 6.5 h; Stage #2: With hydrogenchloride In water at 0℃; for 1 h;	Step B; 4-Amino-2.3-difluoro-5-nitrobenzoic acid; To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (167.2 g, 0.756 mol, 1 equiv.) in 400 mL of distilled water was added concentrated ammonium hydroxide (28 percent NH₃ solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv), ensuring that internal temperature was below 6.0 °C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90percent complete as determined by HPLC, the mixture was cooled in an ice-water bath, and concentrated HCl (350 mL) was then added dropwise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and then filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 ⁰C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 apercent (220 nm) and 96.96 apercent (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 apercent (220 nm) and 95.40 apercent (254 nm). Combined yield of 4-amino-2,3-difluoro-5- nitrobenzoic acid was 144.8 g (88 percent). ¹H NMR (400 MHz, DMSO-d₆) δ 8.0 (2H, br s, NH₂) 8.42 (IH, dd, J 1.5, 7.6, Ar-H); ¹⁹F NMR (376 MHz, DMSO- d₆) δ -153.9, -129.0. ¹³C NMR (100 MHz, DMSO-d₆) δ 106 (Q d, J 10), 126 (CH), 128 (C), 140 (C-F, dd, J241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR v_mjcm^~l 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected. EPO <DP n="52"/>
88%	Stage #1: With ammonia In water at 6 - 20℃; for 5.83333 - 7.33333 h; Stage #2: With hydrogenchloride In water at 0℃; for 1 h;	To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (2) (167.2 g, 0.756 mol, 1 equiv) in 400 mL of distilled water EPO <DP n="65"/>was added concentrated ammonium hydroxide (28percent NH₃ solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv.) ensuring that internal temperature was below 6.0 ⁰C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90percent complete by HPLC, the reaction mixture was cooled in an ice- water bath and concentrated HCl (350 mL) was then added dropwise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 °C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 apercent (220 nm) and 96.96 apercent (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 apercent (220 nm) and 95.40 apercent (254 nm). Combined yield of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) was 144.8 g (88percent). ¹H NMR (400 MHz, d₆ DMSO) δ 8.0 (2H₅ br s, NH₂) 8.42 (IH, dd, J 1.5, 7.6, Ar-H). ¹⁹F NMR (376 MHz, d₆ DMSO) δ -153.9, -129.0. ¹³C NMR (100 MHz, d₆ DMSO) δ 106 (C, d, J 10), 126 (CH), 128 (C), 140 (C-F, dd, J 241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR v^/cm^"1 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected.; To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (2) (167.2 g, 0.756 mol, 1 equiv) in 400 niL of distilled water was added concentrated ammonium hydroxide (28percent NH₃ solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv.) ensuring that internal temperature was below 6.0 °C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90percent complete by HPLC, the reaction mixture was cooled in an ice- water bath and concentrated HCl (350 mL) was then added drop-wise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 °C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 apercent (220 nm) and 96.96 apercent (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 apercent (220 nm) and 95.40 apercent (254 nm). Combined yield of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) was 144.8 g (88percent). ¹H NMR (400 MHz, d₆ DMSO) δ 8.0 (2H, br s, NH₂) 8.42 (IH, dd, J 1.5, 7.6, Ar-H). ¹⁹F NMR (376 MHz, d₆ DMSO) δ -153.9, -129.0. ¹³C NMR (100 MHz, d₆ DMSO) δ 106 (C, d, J 10), 126 (CH), 128 (C), 140 (C-F₅ dd, J241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR v^/cm^"1 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected.
64%	Stage #1: With ammonia In water for 0.0833333 h; Heating / reflux Stage #2: With hydrogenchloride In water	Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) was dissolved in concentrated ammonium hydroxide (25 ml) to give instantly a yellow solution. A precipitate began to form within five minutes, after which time the mixture was acidified to pH 0 with concentrated aqueous hydrochloric acid. A yellow precipitate rapidly formed. The mixture was heated to boiling and was filtered hot. The yellow solids were washed with 10percent aqueous hydrochloric acid and were suction dried to afford 0.47 g of a yellow powder; 64percent yield; ¹H-NMR (400 MHz; DMSO) δ 13.32 (s, 1H), 8.36 (d, 1H, J=7.6 Hz), 7.98 (s, 2H); ¹⁹F-NMR (376 MHz; DMSO) δ -128.69 to -128.76 (m), -153.60 (d).
95%	With hydrogenchloride; ammonium hydroxide In water	Step B 4-Amino-2,3-difluoro-5-nitro-benzoic acid Ammonium hydroxide solution (~30percent in water) (35 ml, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0° C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0° C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3*50 ml). The combined organic extracts are dried (MgSO₄) and concentrated under reduced pressure to give 14 g (95percent) of pure desired product.

Reference： [1] Patent: US2004/116710, 2004, A1, . Location in patent: Page 6; 16
[2] Patent: WO2007/76245, 2007, A2, . Location in patent: Page/Page column 18-19
[3] Patent: US2003/232869, 2003, A1, . Location in patent: Page 9; 16
[4] Patent: WO2013/142182, 2013, A2, . Location in patent: Page/Page column 21; 22
[5] Patent: WO2007/2092, 2007, A1, . Location in patent: Page/Page column 50
[6] Patent: WO2007/2157, 2007, A2, . Location in patent: Page/Page column 2; 63; 64; 76
[7] Patent: US6469004, 2002, B1,
[8] Patent: US7030119, 2006, B1, . Location in patent: Page/Page column 39-40
[9] Patent: US2003/216460, 2003, A1,

[ 197520-71-1 ] Synthesis Path-Downstream 1~58

1
[ 61079-72-9 ]
[ 197520-71-1 ]

Yield	Reaction Conditions	Operation in experiment
97.1%	With sulfuric acid; nitric acid; at 90 - 95℃; for 3.5h;	A stirred solution of 2,3,4-trifluorobenzoic acid (5) (10 g, 56.8 mmol) in concentrated H2SO4 (98%, 33.0 g) was treated dropwise with the mixture of concentrated HNO3 (65%, 6.0g) and H2SO4 (98%, 6.3g) for 3.5 h between 90 and 95 C. The reaction progress was monitored by TLC (30% ethylacetate in hexane). After completion of the reaction, the reaction mixture was cooled to room temperature and ice-water (50g) was added. The precipitation was separated by centrifugation and dried between 50 and 55 C for 8 h. The crude product was purified by column chromatography using 20% ethylacetate:hexane as eluent. The solvent was removed under reduced pressure to afford a white solid 6 (12.2 g) in 97.1% yield.
92%	With sulfuric acid; nitric acid; for 2.5h;	A 3 litre three neck round bottom flask was charged with 125 ml H2SO4. Fuming nitric acid was added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) was added in 5 g portions over 90 minutes. The dark brownish yellow solution was stirred for 60 minutes at which time the reaction was complete. The reaction mixture was poured into 1 litre of an ice: water mixture and extracted with diethyl ether (3 x 600 ml). The combined extracts were dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 min after which time it was filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-I) detected.
92%	With sulfuric acid; nitric acid; for 2.5h;	A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3×600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-1) detected.

92%	With sulfuric acid; nitric acid; for 2.5h;	2, 3,4-Trifluoro-5-nitro-benzoic acid 2A 3 liter three neck round bottom flask is charged with 125 ml H2504. Fuming nitricacid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1(25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solutionis stirred for 60 mm at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3 x 600 ml). The combinedorganic extracts are dried (Mg504) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 mm after which time it is filtered togive 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) nilz 220 (M-1) detected.
88%	With sulfuric acid; nitric acid; at 90℃; for 5h;	Compound 1 (5 g, 28.41 mmol) was added to a solution of concentrated sulfuric acid (15 ml) and heated to 90 C.Then, a mixed acid of concentrated H2SO4 (3.2 g, 98%) and HNO3 (3 g, 68%) was added dropwise, and reacted for 5 hours.After cooling to room temperature, the mixture was poured into EtOAc (EtOAc)EtOAc.An oil of 5.5 g was obtained in a yield of 88%.
78%	With sulfuric acid; nitric acid; In water;	Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO)delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95,1 23.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid; In water;	Step a Preparation of 5-Nitro-2,3,4-trifluorobenzoic Acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO) delta14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid; In water;	Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 % yield; m.p.;1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid; In water;	Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 % yield; m.p.;1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0. 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid; for 0.75h;	To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta -120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
75%	With sulfuric acid; nitric acid; at 0 - 20℃; for 6h;	Example 1; Preparation of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid; [00238] Step A; 2,3,4-Trifluoro-5-mtrobenzoic acid; Fuming HNO3 90% (549.0 g,7.84 mol corrected for 90% wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution OfHNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice- water bath cooling over an hour. When addition was complete, the reaction solution was allowed to warm to room temperature. After 5 hours, the reaction was complete as determined by HPLC and the reaction mixture (brown solution) was poured into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice over 10 minutes. The yellow slurry was cooled to 14 C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven-dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 0C under high vacuum overnight to yield 1035.9 g (75%) of 2,3,4-trifluoro-5-nitrobenzoic acid as a yellowish solid. HPLC was 98 a% (220 nm) and 100% (254 nm). 1H NMR (400 MHz, DMSO-d6) delta 8.44 (IH, apparent dt, J 1.9, 7, Ar-H); 19F NMR (376 EPO <DP n="51"/>MHz, DMSOd6) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz, DMSO-d6) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F, dd, J 265, 13), 154 (C-F, dd, J 265, 10), 163 (COOH). IR v^/cnf1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
75%	With sulfuric acid; nitric acid; at 0 - 20℃; for 6.3h;Product distribution / selectivity;	Fuming HNO3 90% (549.0 g,7.84 mol corrected for 90% wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution Of HNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice-water bath cooling over an hour. Upon complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was complete by HPLC and the reaction mixture (brown solution) was poured over 10 minutes into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow slurry was cooled to 14 C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven- dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 0C under high vacuum overnight to yield 1035.9 g (75%) of compound 2 as a yellowish solid. HPLC was 98 a% (220 nm) and 100% (254 nm). 1H NMR (400 MHz, d6 DMSO) delta 8.44 (IH, apparent dt, J 1.9, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz, d6 DMSO) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, 7251, 10), 148 (C-F5 dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR vmJcmA 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
74.3%	With Hexamethyldisiloxane; sulfuric acid; nitric acid; at 15 - 25℃; for 6.25h;Product distribution / selectivity;	Trifluorobenzoic acid (70 Kg5 398 MoI) in sulphuric acid (96 wt%; 194 L) and hexamethyldisiloxane (6,5 Kg5 40 MoI)5 at 23 0C, was added a 1:1 mixture of sulphuric acid (96 wt%) and nitric acid (98 wt%) (total 70.1 Kg)5 over 75 min. The temperature of the reaction mixture was maintained between 15 and 25 0C during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg)5 keeping the temperature of the ice micture below 0 C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0 0C5 then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L)5 and the solid was then suspended in water (280 L) and stirred for 2 hours at 0 C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45 0C for 2 days, to provide 2,354-Trifluoro-5-nitro benzoic acid (69.4 Kg5 74.3% yiled). 1H NMR (400 MHz5 d6 DMSO) delta 8.44 (IH, apparent dt, J 2, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz5 d6 DMSO) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F5 dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR vmjcm l 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
50%	With sulfuric acid; nitric acid; In sulfuric acid; at 5 - 20℃; for 2h;	Example 1 5-FLUORO-6-(2-FLUORO-4-IODO-DHENYLAMINO)-3-METHYL-3H-BENZOIMIDAZOLE-5-CARBOXYLIC ACID (2-- OH-ETHOXY)-AMIDE Step A: Preparation of 2. 3. 4-trifluoro-5-nitrobenzoic acid Fuming HNO3 was added dropwise to the cold (5 TO-10 C) conc. H2SO4 (5L) and stirred in a three-necked round bottom flask (20L), maintaining the temperature between 5 to- 10 C. Then was added 2, 3, E-TRIFTUOROBENZOIC acid (1 kg, 5.6 mol) in portions, maintaining the temperature at 5O C and after completion of the addition the reaction mixture was allowed to warm to room temperature, stirred for 2h and (the suspension becomes light yellow solution) then poured into 30 kg of crushed ice. The mixture was extracted with ether (3 X 4.0 L) and the organic extracts were washed with water (2 X 2L), brine (2.0 L), dried over anhydrous MGS04, filtered and evaporated under vacuum. The residue (cream colored solid) obtained is re-crystallized from hot chloroform provided the title compound as a solid (yellow). Yield : 880G (50%), mp. 128-129 OC
	With sulfuric acid; nitric acid; for 2.5h;	Example 1; Step A: 2,3,4-Trifluoro-5-nitro-benzoic acid 2 . A 3 liter three neck round bottom flask is charged with 125 mL H2SO4. Fuming nitric acid is added (8.4 mL, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 minutes at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3×600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 minutes after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-1) detected.
29 g (92%)	With sulfuric acid; nitric acid;	Step A 2,3,4-Trifluoro-5-nitro-benzoic acid A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3*600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid.
	With sulfuric acid; potassium nitrate; In hexane;	(1) 2,3,4-Trifluoro-5-nitrobenzoic acid: 2,3,4-Trifluorobenzoic acid (1 g) was added to sulfuric acid (5 ml), and potassium nitrate (630 mg) was gradually added to the mixture under cooling on ice. The resultant mixture was stirred overnight at room temperature, and the reaction mixture was poured onto crushed ice. The mixture was extracted with diethyl ether, and the organic phase was dried over magnesium sulfate. The solvent was removed through distillation, and n-hexane was added to the residue, to thereby collect the solid of the title compound (1 g) by filtration. Form: colorless powder Melting point: 127-135 C. 1 H--NMR(CDC kappa3)delta; 8.67-8.71(m, 1H)
	With potassium nitrate; In hexane; sulfuric acid;	Referential Example 5 Synthesis of 2,3,4-Trifluoro-5-nitrobenzoic Acid 2,3,4-Trifluorobenzoic acid (2.5 g) was dissolved in concentrated sulfuric acid (15 ml). Potassium nitrate (1.62 g) was added to the solution under ice cooling. The temperature of the reaction mixture was (given back to room temperature to conduct stirring for 2 days. The reaction mixture was poured into ice water (300 ml) and extracted with ether (200 ml). An organic layer was dried and concentrated. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (3.06 g) as a pale yellow powder. 1 H-NMR (d6 -DMSO) delta: 8.40-8.47(m,1H).
	With sulfuric acid; nitric acid; at 5 - 20℃; for 2h;	00128] Step A: 2,3,4-Trifluoro-5-nitrobenzoic acid:[00129] Fuming nitric acid (1.7 ml) is added dropwise to concentrated sulfuric acid (25 ml) while maintaining the temperature at 5 - 10 C. 2,3,4-Trifluorobenzoic acid (5 g, 28 mmoles) is added in small portion to this solution while keeping the reaction temperature at 5 C. After completion the reaction mixture is stirred at room temperature for an additional 2 hours and poured into ice. The mixture is extracted with ether (3 x 75 ml). The organic layers are combined, washed with brine, dried (MgSO4). The solvent is removed, and the crude product is recrystallized from hot chloroform to obtain the title compound.

Reference： [1]Journal of Chemical Research,2015,vol. 39,p. 326 - 327
[2]Patent: WO2007/76245,2007,A2 .Location in patent: Page/Page column 18
[3]Patent: US2003/232869,2003,A1 .Location in patent: Page 9; 16
[4]Patent: WO2013/142182,2013,A2 .Location in patent: Page/Page column 21
[5]Patent: CN109438362,2019,A .Location in patent: Paragraph 0100-0105
[6]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917
[7]Patent: US6469004,2002,B1
[8]Patent: US6506798,2003,B1
[9]Patent: EP1202724,2003,B1
[10]Patent: EP1202724,2003,B1
[11]Patent: US7030119,2006,B1 .Location in patent: Page/Page column 39
[12]Patent: WO2007/2092,2007,A1 .Location in patent: Page/Page column 49-50
[13]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 2; 63
[14]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 68
[15]Patent: WO2005/9975,2005,A2 .Location in patent: Page/Page column 51-52
[16]Patent: US2004/116710,2004,A1 .Location in patent: Page 9; 16
[17]Patent: US2003/216460,2003,A1
[18]Patent: US5994575,1999,A
[19]Patent: US6136823,2000,A
[20]Patent: WO2008/89459,2008,A1 .Location in patent: Page/Page column 42

2
[ 197520-71-1 ]
2,3,4-trifluoro-5-nitro-benzoyl chloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917

3
[ 197520-71-1 ]
2,3,4-trifluoro-5-nitro-benzoyl azide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917

4
[ 197520-71-1 ]
[ 535170-19-5 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917

5
[ 197520-71-1 ]
[ 535170-16-2 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917

6
[ 197520-71-1 ]
[ 179739-47-0 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917

7
[ 197520-71-1 ]
[ 535170-23-1 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917

8
[ 197520-71-1 ]
7-((S)-3-Amino-pyrrolidin-1-yl)-1-(5-amino-2,3,4-trifluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917

9
[ 197520-71-1 ]
3-(5-<i>tert</i>-butoxycarbonylamino-2,3,4-trifluoro-phenylamino)-2-(2,6-dichloro-5-fluoro-pyridine-3-carbonyl)-acrylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917

10
[ 197520-71-1 ]
[ 284030-57-5 ]

Yield	Reaction Conditions	Operation in experiment
95%		Step B: 4-Amino-2,3-difluoro-5-nitro-benzoic acid 3 [0122] Ammonium hydroxide solution (30% in water) (35 mL, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 mL water at 0 C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 hours, the reaction mixture is cooled to 0 C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.
95%		Ammonium hydroxide solution (-30% in water) (35 ml, 271 mmol) was added to a solution of 2,3,4-trifluoro-5- nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0 0C with stirring. Upon completion of the ammonium hydroxide addition, the reaction mixture was warmed to room temperature with stirring. After 2.5 hours, the reaction mixture was cooled to 0 0C and concentrated HCl was carefully added until pH of reaction mixture was 0. The reaction mixture was diluted <n="20"/>with water (30 ml) and extracted with diethyl ether (3 x 50 ml). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (-) m/z 217 (M-I) detected.
95%		Ammonium hydroxide solution (30% in water) (35 ml, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 ml water at 0 C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3×50 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.

95%	With ammonium hydroxide; In water; at 0 - 20℃; for 2.5h;	4-Amino-2, 3-difluoro-5-nitro-benzoic acid 3Ammonium hydroxide solution (-30% in water) (35 ml, 271 mmol) is added to asolution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 ml water at 0 C with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 C andconcentrated HC1 is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3 x 50 ml). combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.
88%		Step B; 4-Amino-2.3-difluoro-5-nitrobenzoic acid; To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (167.2 g, 0.756 mol, 1 equiv.) in 400 mL of distilled water was added concentrated ammonium hydroxide (28 % NH3 solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv), ensuring that internal temperature was below 6.0 C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90% complete as determined by HPLC, the mixture was cooled in an ice-water bath, and concentrated HCl (350 mL) was then added dropwise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and then filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 0C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 a% (220 nm) and 96.96 a% (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 a% (220 nm) and 95.40 a% (254 nm). Combined yield of 4-amino-2,3-difluoro-5- nitrobenzoic acid was 144.8 g (88 %). 1H NMR (400 MHz, DMSO-d6) delta 8.0 (2H, br s, NH2) 8.42 (IH, dd, J 1.5, 7.6, Ar-H); 19F NMR (376 MHz, DMSO- d6) delta -153.9, -129.0. 13C NMR (100 MHz, DMSO-d6) delta 106 (Q d, J 10), 126 (CH), 128 (C), 140 (C-F, dd, J241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR vmjcm~l 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected. EPO <DP n="52"/>
88%		To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (2) (167.2 g, 0.756 mol, 1 equiv) in 400 mL of distilled water EPO <DP n="65"/>was added concentrated ammonium hydroxide (28% NH3 solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv.) ensuring that internal temperature was below 6.0 0C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90% complete by HPLC, the reaction mixture was cooled in an ice- water bath and concentrated HCl (350 mL) was then added dropwise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 a% (220 nm) and 96.96 a% (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 a% (220 nm) and 95.40 a% (254 nm). Combined yield of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) was 144.8 g (88%). 1H NMR (400 MHz, d6 DMSO) delta 8.0 (2H5 br s, NH2) 8.42 (IH, dd, J 1.5, 7.6, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -129.0. 13C NMR (100 MHz, d6 DMSO) delta 106 (C, d, J 10), 126 (CH), 128 (C), 140 (C-F, dd, J 241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR v^/cm"1 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected.; To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (2) (167.2 g, 0.756 mol, 1 equiv) in 400 niL of distilled water was added concentrated ammonium hydroxide (28% NH3 solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv.) ensuring that internal temperature was below 6.0 C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90% complete by HPLC, the reaction mixture was cooled in an ice- water bath and concentrated HCl (350 mL) was then added drop-wise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 a% (220 nm) and 96.96 a% (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 a% (220 nm) and 95.40 a% (254 nm). Combined yield of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) was 144.8 g (88%). 1H NMR (400 MHz, d6 DMSO) delta 8.0 (2H, br s, NH2) 8.42 (IH, dd, J 1.5, 7.6, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -129.0. 13C NMR (100 MHz, d6 DMSO) delta 106 (C, d, J 10), 126 (CH), 128 (C), 140 (C-F5 dd, J241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR v^/cm"1 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected.
81%	With ammonium hydroxide; In water; at 0℃; for 6h;	At 0 C,NH3·H2O (2.38 g, 67.87 mmol) was slowly added dropwise to an aqueous solution of compound 2 (3 g, 13.57 mmol).After the addition was completed, the reaction was continued for 6 hours. The reaction was quenched by the addition of 1 M hydrochloric acid until the pH of the solution was adjusted to about 2, and extracted with dichloromethane (60 ml × 3).The solvent was removed to give a pale yellow solid product (2.4 g, yield 81%)
64%	In ammonium hydroxide;	Step b Preparation of 4-amino-2,3-difluoro-5-nitrobenzoic acid Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) was dissolved in concentrated ammonium hydroxide (25 ml) to give instantly a yellow solution. A precipitate began to form within five minutes, after which time the mixture was acidified to pH 0 with concentrated aqueous hydrochloric acid. A yellow precipitate rapidly formed. The mixture was heated to boiling and was filtered hot. The yellow solids were washed with 10% aqueous hydrochloric acid and were suction dried to afford 0.47 g of a yellow powder; 64% yield; 1H-NMR (400 MHz; DMSO) delta13.32 (s, 1H), 8.36 (d, 1H, J=7.6 Hz), 7.98 (s, 2H); 19F-NMR (376 MHz; DMSO) delta-128.69 to -128.76 (m), -153.60 (d).
64%		Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) was dissolved in concentrated ammonium hydroxide (25 ml) to give instantly a yellow solution. A precipitate began to form within five minutes, after which time the mixture was acidified to pH 0 with concentrated aqueous hydrochloric acid. A yellow precipitate rapidly formed. The mixture was heated to boiling and was filtered hot. The yellow solids were washed with 10% aqueous hydrochloric acid and were suction dried to afford 0.47 g of a yellow powder; 64% yield; 1H-NMR (400 MHz; DMSO) delta 13.32 (s, 1H), 8.36 (d, 1H, J=7.6 Hz), 7.98 (s, 2H); 19F-NMR (376 MHz; DMSO) delta -128.69 to -128.76 (m), -153.60 (d).
14 g (95%)	With hydrogenchloride; ammonium hydroxide; In water;	Step B 4-Amino-2,3-difluoro-5-nitro-benzoic acid Ammonium hydroxide solution (~30% in water) (35 ml, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0 C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3*50 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product.

Reference： [1]Patent: US2004/116710,2004,A1 .Location in patent: Page 6; 16
[2]Patent: WO2007/76245,2007,A2 .Location in patent: Page/Page column 18-19
[3]Patent: US2003/232869,2003,A1 .Location in patent: Page 9; 16
[4]Patent: WO2013/142182,2013,A2 .Location in patent: Page/Page column 21; 22
[5]Patent: WO2007/2092,2007,A1 .Location in patent: Page/Page column 50
[6]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 2; 63; 64; 76
[7]Patent: CN109438362,2019,A .Location in patent: Paragraph 0100-0103; 0106-0107
[8]Patent: US6469004,2002,B1
[9]Patent: US7030119,2006,B1 .Location in patent: Page/Page column 39-40
[10]Patent: US2003/216460,2003,A1

11
[ 29632-74-4 ]
[ 197520-71-1 ]
[ 836602-26-7 ]

Yield	Reaction Conditions	Operation in experiment
55.35%		B: Preparation of the 3. 4-DIFLUORO-2- (2-FLUORO-4-IODO-PHENYLAMINO)-5-NITRO-BENZOIC acid A stirred solution of 2,3, 4-trifluoro-5-nitrobenzoic acid (400 g, 1.9 mol) in dry THF (6L) under nitrogen was cooled to-58 C and a solution of 2.0 L 1.0 M LIHMDS (1. OU, 2L, 2.0 mol) was added dropwise at-58 C. This reaction mixture (yellow solution turned into yellow orange suspension) was designated as reaction mixture A. In a separate reaction flask, 2-FLUORO-4-IODOANILINE (400G, 1.0 mol) in THF (4L) was cooled TO-58 C under nitrogen and a solution LIHMDS (1. 0M, 3.65L, 3.6 mol) was added dropwise AT-58 C (the yellow solution turned into a white suspension). This reaction mixture was designated as mixture B. Both the reaction mixtures A and B were stirred for 45 min. , maintaining the temperature AT-58 C and mixture A was transferred into reaction mixture B by a canula. The resulting orange suspension was stirred for 1 h AT-58 C, then allowed to warm-up to room temperature and stirred overnight under nitrogen. The reaction mixture was cooled to - 10 C and adjusted to pH 1 by bubbling HCI gas. The white solid separated was filtered through a short bed of CELITE, washed with THF (3L) and the filtrate (brown) was evaporated under vacuum. The residue (yellow orange solid) obtained was triturated with 10% aq. HCI (3L) solution and the solid separated was filtered, washed with 10% aq HCI (2X1L), water (4 X 1.0 L) and the wet solid was taken in toluene (1 L). The toluene solution was evaporated to remove water and the residue obtained was digested in hot methanol (3.0 L), filtered, washed with methanol (2L) then dried to give the title compound as solid (yellow). Yield: 543. 9G (55. 35%).
		[00130] Step B: 3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-5-nitrobenzoic acid:[ 00131] To a solution of 2-fluoro-4-iodoaniline (2.9 g, 11.8 mmoles) in 50 ml anhydrous THF at -60 C, 40 ml of a 1M solution of LHMDS in THF (40 mmoles) is added dropwise. In a separate flask, 2,3,4-trifluoro-5- nitrobenzoic acid (5 g, 22.6 mmoles), previously dissolved in THF (50 ml), is treated, at -60 C, with 25 ml of a 1M solution of LHMDS in THF (25 mmoles). Both solutions are stirred at -78 C for 45 min and the second solution is transferred via cannula to the first reaction mixture. After completion of the addition the resulting mixture is stirred under argon at room temperature for 15 hours. The reaction mixture is quenched with water, then 1N HCl is added (pH = 0-1) followed by brine (100 ml). The crude material is extracted with THF (3 x 100 ml), the organic layers are combined and dried (Na2SO4) and the solvent is removed to give the title compound.

Reference： [1]Patent: WO2005/9975,2005,A2 .Location in patent: Page/Page column 52
[2]Patent: WO2008/89459,2008,A1 .Location in patent: Page/Page column 42

Yield	Reaction Conditions	Operation in experiment
		Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid Same as for Example 1, Step a.
		Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid Same as for Example 1, Step a.

13
[ 197520-71-1 ]
[ 284030-63-3 ]

Yield	Reaction Conditions	Operation in experiment
22%	In sodium hydroxide;	Step b Preparation of 2,3-difluoro4-hydroxy-5-nitrobenzoic acid The solid <strong>[197520-71-1]5-nitro-2,3,4-trifluorobenzoic acid</strong> (1.00 g, 0.00452 mol) was dissolved in 10 wt. % aqueous sodium hydroxide solution. The mixture was clear deep orange. After standing under ambient conditions for several minutes, the mixture was quenched with concentrated aqueous hydrochloric acid until strongly acidic (pH 0). A white solid precipitated which was isolated by vacuum filtration and dried with suction to afford 0.40 g of an off-white solid. This solid was recrystallized from chloroform (20 ml) to afford 0.22 g of an off-white crystalline powder; 22% yield; MS (APCl-) 218 (M-1, 100).
22%		The solid <strong>[197520-71-1]5-nitro-2,3,4-trifluorobenzoic acid</strong> (1.00 g, 0.00452 mol) was dissolved in 10 wt. % aqueous sodium hydroxide solution. The mixture was clear deep orange. After standing under ambient conditions for several minutes, the mixture was quenched with concentrated aqueous hydrochloric acid until strongly acidic (pH 0). A white solid precipitated which was isolated by vacuum filtration and dried with suction to afford 0.40 g of an off-white solid. This solid was recrystallized from chloroform (20 ml) to afford 0.22 g of an off-white crystalline powder; 22% yield; MS (APCl-) 218 (M-1, 100).

Reference： [1]Patent: US6469004,2002,B1
[2]Patent: US7030119,2006,B1 .Location in patent: Page/Page column 44-45

14
[ 42016-93-3 ]
[ 197520-71-1 ]
[ 219796-67-5 ]

Yield	Reaction Conditions	Operation in experiment
1%	With lithium diisopropyl amide; In tetrahydrofuran; tetrahydrofuran-heptane-ethylbenzene; ethanol; dichloromethane;	Step b Preparation of 2,4-bis-(2-Chloro-4-iodo-phenylamino)-3-fluoro-5-Nitrobenzoic Acid To a stirring solution comprised of 2-chloro-4-iodoaniline (Lancaster, 98%, 12.33 g, 0.04864 mol) in tetrahydrofuran (20 ml) at -78 C. under nitrogen was added a 2.0 M lithium diisopropylamide solution in tetrahydrofuran-heptane-ethylbenzene (Aldrich, 35 ml, 0.070 mol) with a syringe. The addition formed a thick suspension. After five minutes of stirring, a solution comprised of <strong>[197520-71-1]5-nitro-2,3,4-trifluorobenzoic acid</strong> (5.00 g, 0.0226 mol) in tetrahydrofuran (30 ml) was added with a syringe to give a dark reaction mixture. The cold bath was removed and the reaction mixture stirred for 20 minutes. The cool reaction mixture was poured into ether (600 ml) containing an excess of hydrogen chloride. The red solution instantly turned to a yellow suspension as a precipitate formed. This precipitate was removed by vacuum filtration. The filtrate was concentrated in vacuo to a red powder (10.5 g). The red powder was triturated with boiling chloroform (800 ml). The triturated solids were collected by vacuum filtration to give an orange powder (2.42 g). The mother liquor from the trituration was concentrated in vacuo to give a red-orange solid (ca. 10 g undried). This solid was loaded onto a flash silica column. Elution with dichloromethane removed some impurities. Continuing elution with 1% methanol in dichloromethane afforede ca. 4 g of a red solid. This red solid was dissolved in hot absolute ethanol (100 ml). The solution was boiled down to 50 ml before dilution to 300 ml with hexanes. This solution was boiled to 150 ml and rediluted to 300 ml with hexanes to produce slight turbidity. The mixture was cooled in the refrigerator for three days, affording a yellow precipitate. The precipitate was collected by vacuum filtration and was dried with suction to afford 0.15 g of a yellow solid; 1% yield; 1H-NMR (400 MHz; DMSO) delta 8.94 (s, 1H), 8.55 (s, 1H), 7.79 (d, 2H, J=2.0 Hz), 7.61-7.57 (m, 2H), 6.90 (dd, 1 H, J=8.5, 3.9 Hz), 6.84 (dd, 1H, J=8.3, 6.6 Hz); 19F-NMR (376 MHz; DMSO) delta-122.62 (s); MS (APCI+) 692 (6), 691 (8), 690 (31), 689 (10), 688 (55), 171 (47), 130 (100); (APCI-) 691 (4), 690 (12), 689 (14), 688 (70), 687 (32), 686 (100), 506 (50), 453 (97); IR (KBr) 1523 cm-1; Anal. calcd/found for: C19H10Cl2Fl2N3O4 C, 33.17/33.32; H, 1.47/1.73; N, 6.11/5.73; Cl 10.31/10.04; F, 2.76/3.70; I, 36.89134.32.
1%	With lithium diisopropyl amide; In tetrahydrofuran; tetrahydrofuranheptane-ethylbenzene; ethanol; dichloromethane;	Step b: Preparation of 2,4-bis-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitrobenzoic acid To a stirring solution comprised of 2-chloro-4-iodoaniline (Lancaster, 98 %, 12.33 g, 0.04864 mol) in tetrahydrofuran (20 ml) at -78 C under nitrogen was added a 2.0 M lithium diisopropylamide solution in tetrahydrofuranheptane-ethylbenzene (Aldrich, 35 ml, 0.070 mol) with a syringe. The addition formed a thick suspension. After five minutes of stirring, a solution comprised of <strong>[197520-71-1]5-nitro-2,3,4-trifluorobenzoic acid</strong> (5.00 g, 0.0226 mol) in tetrahydrofuran (30 ml) was added with a syringe to give a dark reaction mixture. The cold bath was removed and the reaction mixture stirred for 20 minutes. The cool reaction mixture was poured into ether (600 ml) containing an excess of hydrogen chloride. The red solution instantly turned to a yellow suspension as a precipitate formed. This precipitate was removed by vacuum filtration. The filtrate was concentrated in vacuo to a red powder (10.5 g). The red powder was triturated with boiling chloroform (800 ml). The triturated solids were collected by vacuum filtration to give an orange powder (2.42 g). The mother liquor from the trituration was concentrated in vacuo to give a red-orange solid (ca. 10 g undried). This solid was loaded onto a flash silica column. Elution with dichloromethane removed some impurities. Continuing elution with 1 % methanol in dichloromethane afforede ca. 4 g of a red solid. This red solid was dissolved in hot absolute ethanol (100 ml). The solution was boiled down to 50 ml before dilution to 300 ml with hexanes. This solution was boiled to 150 ml and rediluted to 300 ml with hexanes to produce slight turbidity. The mixture was cooled in the refrigerator for three days, affording a yellow precipitate. The precipitate was collected by vacuum filtration and was dried with suction to afford 0.15 g of a yellow solid; 1 % yield; 1H-NMR (400 MHz; DMSO) delta 8.94 (s, 1H), 8.55 (s, 1H), 7.79 (d, 2H, J=2.0 Hz), 7.61-7.57 (m, 2H), 6.90 (dd, 1H, J=8.5, 3.9 Hz), 6.84 (dd, 1H, J=8.3, 6.6 Hz); 19F-NMR (376 MHz; DMSO) delta -122.62 (s); MS (APCI+) 692 (6), 691 (8), 690 (31), 689 (10), 688 (55), 171 (47), 130 (100); (APCI-) 691 (4), 690 (12), 689 (14), 688 (70), 687 (32), 686 (100), 506 (50), 453 (97); IR (KBr) 1523 cm-1; Anal. calcd/found for: C19H10Cl2FI2N3O4 C, 33.17/33.32; H, 1.47/1.73; N, 6.11/5.73; Cl, 10.31/10.04; F, 2.76/3.70; I, 36.89/34.32.
1%	With lithium diisopropyl amide; In tetrahydrofuran; tetrahydrofuranheptane-ethylbenzene; ethanol; dichloromethane;	Step b: Preparation of 2,4-bis-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitrobenzoic acid To a stirring solution comprised of 2-chloro-4-iodoaniline (Lancaster, 98 %, 12.33 g, 0.04864 mol) in tetrahydrofuran (20 ml) at -78 C under nitrogen was added a 2.0 M lithium diisopropylamide solution in tetrahydrofuranheptane-ethylbenzene (Aldrich, 35 ml, 0.070 mol) with a syringe. The addition formed a thick suspension. After five minutes of stirring, a solution comprised of <strong>[197520-71-1]5-nitro-2,3,4-trifluorobenzoic acid</strong> (5.00 g, 0.0226 mol) in tetrahydrofuran (30 ml) was added with a syringe to give a dark reaction mixture. The cold bath was removed and the reaction mixture stirred for 20 minutes. The cool reaction mixture was poured into ether (600 ml) containing an excess of hydrogen chloride. The red solution instantly turned to a yellow suspension as a precipitate formed. This precipitate was removed by vacuum filtration. The filtrate was concentrated in vacuo to a red powder (10.5 g). The red powder was triturated with boiling chloroform (800 ml). The triturated solids were collected by vacuum filtration to give an orange powder (2.42 g). The mother liquor from the trituration was concentrated in vacuo to give a red-orange solid (ca. 10 g undried). This solid was loaded onto a flash silica column. Elution with dichloromethane removed some impurities. Continuing elution with 1 % methanol in dichloromethane afforede ca. 4 g of a red solid. This red solid was dissolved in hot absolute ethanol (100 ml). The solution was boiled down to 50 ml before dilution to 300 ml with hexanes. This solution was boiled to 150 ml and rediluted to 300 ml with hexanes to produce slight turbidity. The mixture was cooled in the refrigerator for three days, affording a yellow precipitate. The precipitate was collected by vacuum filtration and was dried with suction to afford 0.15 g of a yellow solid; 1 % yield; 1H-NMR (400 MHz; DMSO) delta 8.94 (s, 1H), 8.55 (s, 1H), 7.79 (d, 2H, J=2.0 Hz), 7.61-7.57 (m, 2H), 6.90 (dd, 1H, J=8.5, 3.9 Hz), 6.84 (dd, 1H, J=8.3, 6.6 Hz); 19F-NMR (376 MHz; DMSO) delta -122.62 (s); MS (APCI+) 692 (6), 691 (8), 690 (31), 689 (10), 688 (55), 171 (47), 130 (100); (APCI-) 691 (4), 690 (12), 689 (14), 688 (70), 687 (32), 686 (100), 506 (50), 453 (97); IR (KBr) 1523 cm-1; Anal. calcd/found for: C19H10Cl2Fl2N3O4 C, 33.17/33.32; H, 1.47/1.73; N, 6.11/5.73; Cl, 10.31/10.04; F, 2.76/3.70; I, 36.89/34.32.

Reference： [1]Patent: US6506798,2003,B1
[2]Patent: EP1202724,2003,B1
[3]Patent: EP1202724,2003,B1

15
[ 79-37-8 ]
[ 197520-71-1 ]
[ 197520-72-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzyl alcohol; In diethyl ether; hexane; dichloromethane; water; N,N-dimethyl-formamide; toluene;	(2) N-Benzyloxycarbonyl-2,3,4-trifluoro-5-nitroaniline: <strong>[197520-71-1]2,3,4-Trifluoro-5-nitrobenzoic acid</strong> (1 g) was added to methylene chloride (10 ml) and N,N-dimethylformamide (several ml), and oxalyl chloride (1.2 ml) was added dropwise to the mixture. The resultant mixture was stirred overnight at room temperature, and the reaction mixture was concentrated under reduced pressure. Methylene chloride (10 ml) and N,N-dimethylformamide (10 ml) were added to the resultant residue, and sodium azide (322 mg) was added to the mixture under cooling on ice. The mixture was stirred at room temperature for one hour, and diethyl ether (20 ml), n-hexane (5 ml), and water (50 ml) were added to the reaction mixture, to thereby collect an organic phase, which was dried over magnesium sulfate. The solvent was removed through distillation, and toluene (10 ml) and benzyl alcohol (1 ml) were added to the residue. The mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure, and n-hexane was added to the residue, to thereby collect the solid of the title compound (880 mg) by filtration. Form: yellow powder Melting point: 136-145 C. 1 H--NMR(CDC lambda 3)delta; 5.28(s, 2H), 6.96(brs, 1H), 7.36-7.45(m, 5H), 8.75-8.86(m, 1H)

Reference： [1]Patent: US5994575,1999,A

16
[ 79-37-8 ]
[ 105-53-3 ]
[ 197520-71-1 ]
ethyl 2,3,4-trifluoro-5-nitrobenzoylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With p-toluenesulfonic acid monohydrate; magnesium; In tetrahydrofuran; tetrachloromethane; ethanol; dichloromethane; water; N,N-dimethyl-formamide;	Referential Example 6 Synthesis of Ethyl 2,3,4-Trifluoro-5-nitrobenzoylacetate <strong>[197520-71-1]2,3,4-Trifluoro-5-nitrobenzoic acid</strong> (3.0 g) was dissolved in dichloromethane (20 ml) and N,N-dimethylformamide (0.3 ml). Oxalyl chloride (3 ml) was added dropwise to this solution, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and azeotropic distillation was conducted 3 times with dry tetrahydrofuran. The residue was dissolved in tetrahydrofuran (10 ml). This solution is regarded as Solution A. Magnesium (336 mg) was added to ethanol (1 ml), and carbon tetrachloride (0.1 ml) was added to the resultant mixture. A solution of ethyl malonate (2.25 g) in tetrahydrofuran (10 ml) and ethanol (0.5 ml) was added dropwise to the mixture at the time a reaction started. Thereafter, the reaction mixture was stirred for 4 hours while heating under reflux. The reaction mixture was slowly added dropwise to Solution A at -70 C. The temperature of the reaction mixture was slowly raised to room temperature. The solvent was distilled off under reduced pressure. The residue was extracted with chloroform (50 ml), and the resultant extract was washed with 3N hydrochloric acid. The solvent was distilled off under reduced pressure. Water (30 ml) and p-toluenesulfonic acid monohydrate (0.3 g) were added to the resultant residue, and the mixture was stirred for 3.5 hours while heating under ref lux. The reaction mixture was extracted with chloroform, and an organic layer was dried and then concentrated. The resultant residue was subjected to column chromatography on silica gel (eluent; ethyl acetate:hexane=1:8) to obtain the title compound (1.4 g) as a yellow oil. 1 H-NMR (CDCl3) delta: 1.20-1.40(m,3H), 4.15-4.35(m,2H), 5.88(s), 8.45-8.65(m,1H).

Reference： [1]Patent: US6136823,2000,A

17
[ 61079-72-9 ]
ice-water [ No CAS ]
[ 197520-71-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; nitric acid;	Reference Example 1 A mixed solution of 10.56 g (60 mmol) of 2,3,4-trifluorobenzoic acid and 15.6 ml of sulfuric acid was ice-cooled, and 11.4 ml of a fumed nitric acid was added dropwise thereto at 5 to 30 C. and the mixture was stirred at the same temperature for 5 hours to complete the reaction. After completion of the reaction, the resulting reaction mixture was added to 400 ml of ice-water, and then, extracted twice with 150 ml of ethyl acetate. The combined organic layers were washed with 100 ml of water, dried over anhydrous magnesium sulfate, and then, filtered and evaporated to dryness. The resulting product obtained by evaporation to dryness was added to 50 ml of water and the mixture was stirred to wash the product. After collecting the precipitates by filtration, the precipitates were dried under reduced pressure to obtain 10.0 g (45.2 mmol) of 2,3,4-trifluoro-5-nitrobenzoic acid. Melting point: 134-135 C. 1 H-NMR (DMSO, 400 MHz) delta (ppm)=8.68 (H, ddd, Ar-H)

Reference： [1]Patent: US6160171,2000,A

18
[ 197520-71-1 ]
5-amino-2,3,4-trifluorobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.2%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 7500.75 - 9000.9 Torr; for 6h;Autoclave;	Compound 6 (12.0 g, 54.3 mmol), Pd/C (10%, 1.2g), and methanol (120 mL) were placed ina autoclave (250 mL). The autoclave was purged with H2 three times to remove air, and the reaction mixture was stirred with a balloon of H2 at room temperature for 6.0 h under a pressure between 1.0 and 1.2 MPa. After the reaction, the resultant mixture was transferred into a tube and the solid was separated by centrifugation. The solvent was removed under reduced pressure to afford a white solid 7 (10.2 g) in 98.2% yield.
	palladium-carbon; In ethanol;	Reference Example 2 A mixed solution was obtained by mixing 9.0 g (40.7 mmol) of <strong>[197520-71-1]2,3,4-trifluoro-5-nitrobenzoic acid</strong> obtained in Reference example 1, 100 ml of ethanol and 1.0 g of 20% Pd/C (50% hydrated material) under nitrogen atmosphere. A hydrogen gas was passed through the resulting mixed solution at room temperature to carry out the reaction. After completion of the reaction, the resulting reaction solution was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from hexane-ethyl acetate. The resulting crystals were collected by filtration and dried under reduced pressure to obtain 7.09 g (37.1 mmol) of 5-amino-2,3,4-trifluorobenzoic acid. Melting point: 164.5-166 C. 1 H-NMR (DMSO, 400 MHz) EQU1

Reference： [1]Journal of Chemical Research,2015,vol. 39,p. 326 - 327
[2]Patent: US6160171,2000,A

19
[ 197520-71-1 ]
[ 918321-31-0 ]

Yield	Reaction Conditions	Operation in experiment
86%		A suspension of <strong>[197520-71-1]2,3,4-trifluoro-5-nitrobenzoic acid</strong> (1) (5 g) and ammonium hydroxide (7.7 grams, 25 wt% NH3 in H2O, 4.9 equivalents) in N-methyl pyrrolidinone (12.5 mL) was heated at 80-90 0C in a sealed reactor. During the reaction the mixture became homogeneous and the pressure rose to 0.4 bar. After 1.75 hours, HPLC analysis showed incomplete conversion and a further charge of ammonium hydroxide (2 g, 25 wt % NH3 in H2O) was added, followed by heating at 80-90 0C in the sealed reactor for an additional 1.5 hours. After this time HPLC analysis indicated >99% conversion and the mixture was allowed to cool to room temperature overnight. The contents of the reactor were then added to water (100 mL), producing a homogeneous, brown solution with a pH of 9.4. Acetic acid was then added to the mixture until the pH was 6. After cooling to 0 0C the product was isolated by filtration and washed with a mixture of water (10 mL) and MeOH (10 mL), then dried in a vacuum oven at 50 C, to provide 4.4 g (86% yield) of 2,4-diamino-3-fluoro-5- nitrobenzoic acid (2) (HPLC purity 99.7 a%). 1R NMR (400 MHz, d6 DMSO) delta 7.27 (2H, br s, NH2), 7.31 (2H, br s, NH2), 8.46, (IH, s, Ar-H), 13.10 (IH, br, CO2H). 13C NMR (100 MHz, d6 DMSO) delta 102 (C), 123 (C), 127 (CH), 136 (d, J 229, CF), 138 (C), 143 (CF), 168 (C=O).

Reference： [1]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 75

20
[ 67-56-1 ]
[ 197520-71-1 ]
[ 918321-24-1 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane; at 10 - 30℃; for 5h;Heating / reflux;	2,3,4-Trifluoro-5- nitrobenzoic acid (100 g, 0.452 MoI) was dissolved in methanol (60 mL) at 25-30 0C. To the resulting stirred solution, at 10 C, was added chlorotrimethylsilane (98.3 g, 0.91 MoI, 2 equiv.), maintaining the temperature between 10 and 200C. On completion of the addition the mixture was heated at reflux for 5 hours. At this point 99% (area) conversion to methyl 2,3,4-trifluoro-5-nitrobenzoate (2) was indicated by HPLC analysis. After cooling the mixture to room temperature it was diluted with N-methylpyrrolidone (NMP, 380 mL) and the reaction vessel was placed in an ice-bath. Ammonium hydroxide solution (33 wt% [d 0.88], 164 mL, 144 g, 2.7 MoI) was added to the vigorously stirred mixture, keeping the temperature below 15 C. A yellow precipitate was formed during the addition. The reactor was then closed and heated at 80 0C, with an internal pressure of 2.5 barg. After 5 hour the reaction mixture was cooled to 600C and the pressure was released. The temperature was then increased to 75C, followed by addition of ammonium hydroxide (33 wt% [d 0.88] in water, 53 mL, 47 g. 1.0 MoI), The mixture was then cooled to 500C over 90 min. during with time a yellow precipitate was formed. After a further 1 hour at 50 0C water (400 mL) was added over 1 hour and the resulting suspension was cooled to 25C and filtered. The filter cake was washed once with 1 : 1 NMP/water (540 mL), once with water (540 mL) and then dried in a vacuum oven at 500C for 24 hours, to provide methyl 2,4-diamino-3-fluoro-5-nitrobenzoate 4) (91 g, 88% yield).

Reference： [1]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 69

21
[ 74-89-5 ]
[ 197520-71-1 ]
[ 1380836-70-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	In water; for 3h;Cooling with ice;	A mixture of methylamine (40% aq solution, 0.68 mL, 6.7 mmol), <strong>[197520-71-1]2,3,4-trifluoro-5-nitro-benzoic acid</strong> (0.50 g, 2.3 mmol) and 5 mL water is stirred for 3 h in an ice bath. Then the mixture is acidified with 6M aq HCl and the resulting precipitate is collected by filtration washed with water and dried.Yield: 0.45 g (86%); HPLC Rt=1.13 min (method A). MS m/z: 233 [M+H]+.

Reference： [1]Patent: US2012/149676,2012,A1 .Location in patent: Page/Page column 61

22
[ 197520-71-1 ]
[ 606143-94-6 ]

Reference： [1]Patent: WO2013/142182,2013,A2

23
[ 197520-71-1 ]
[ 284030-58-6 ]

Reference： [1]Patent: WO2013/142182,2013,A2
[2]Patent: CN109438362,2019,A

24
[ 197520-71-1 ]
N-(2-tert-butoxyethoxy)-2,4-diamino-3-fluoro-5-nitrobenzamide [ No CAS ]

Reference： [1]Patent: CN105820124,2016,A

25
[ 1023742-13-3 ]
[ 197520-71-1 ]
N-(2-tert-butoxyethoxy)-2,3,4-trifluoro-5-nitrobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.0%	With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 50℃; for 8h;Green chemistry;	<strong>[197520-71-1]2,3,4-trifluoro-5-nitrobenzoic acid</strong> (25.0g, 0.11mol) and N,N'-carbonyldiimidazole (22.9g, 0.14mol) was dissolved in tetrahydrofuran (110mL), stirred, was added O-(2-tert-butoxyethyl)hydroxylamine (18.1g, 0.14mol), was added dropwise N, N- diisopropylethylamine (58.5g, 0.45mol), the reaction mixture was stirred at 50C for 8h, TLC determine completion of the reaction, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was adjusted to neutral by adding ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, and recrystallized from methanol to give N- (2- tert-butoxide ethoxy) -2,3,4-trifluoro-5-nitrobenzamide, an off-white solid (33.5g), yield 88.0%.

Reference： [1]Patent: CN105820124,2016,A .Location in patent: Paragraph 0032-0035

26
[ 197520-71-1 ]
[ 606143-46-8 ]