[ CAS No. 827-94-1 ]

Name: 827-94-1|2,6-Dibromo-4-nitroaniline|98%
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Product Details of [ 827-94-1 ]

CAS No. :	827-94-1	MDL No. :	MFCD00007639
Formula :	C₆H₄Br₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	295.92 g/mol	Pubchem ID :	-
Synonyms :

Safety of [ 827-94-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302+H312+H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 827-94-1 ]

* 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 [ 827-94-1 ]
Downstream synthetic route of [ 827-94-1 ]

[ 827-94-1 ] Synthesis Path-Upstream 1~10

1
[ 827-94-1 ]
[ 19752-57-9 ]

Reference： [1] Chemistry - A European Journal, 2004, vol. 10, # 24, p. 6433 - 6446
[2] Journal of Organic Chemistry, 2003, vol. 68, # 23, p. 8750 - 8766
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 3, p. 790 - 794[4] Angew. Chem., 2018, vol. 130, p. 798 - 802,5

2
[ 827-94-1 ]
[ 13402-32-9 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[2] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159

3
[ 827-94-1 ]
[ 19230-27-4 ]

Reference： [1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1913, vol. <5> 22 I, p. 823[2] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1914, vol. <5> 23 I, p. 283 Anm.

4
[ 827-94-1 ]
[ 51686-78-3 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[2] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159
[3] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[4] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159

5
[ 827-94-1 ]
[ 626-41-5 ]

Reference： [1] Patent: US2008/280891, 2008, A1,
[2] Patent: WO2008/8059, 2008, A1,

6
[ 827-94-1 ]
[ 74137-36-3 ]

Reference： [1] Patent: US2008/280891, 2008, A1,
[2] Patent: WO2008/8059, 2008, A1,

7
[ 827-94-1 ]
[ 56990-02-4 ]

Reference： [1] Journal of Organic Chemistry, 2003, vol. 68, # 23, p. 8750 - 8766

8
[ 100-01-6 ]
[ 827-94-1 ]
[ 13296-94-1 ]

Reference： [1] Polyhedron, 2013, vol. 52, p. 246 - 254
[2] Tetrahedron, 2009, vol. 65, # 22, p. 4429 - 4439

9
[ 7726-95-6 ]
[ 100-01-6 ]
[ 827-94-1 ]
[ 13296-94-1 ]

Reference： [1] Journal of the American Chemical Society, 1921, vol. 43, p. 311
[2] Journal of the American Chemical Society, 1927, vol. 49, p. 1805
[3] Journal of the Indian Chemical Society, 1927, vol. 4, p. 401[4] Chem. Zentralbl., 1928, vol. 99, # I, p. 490

10
[ 827-94-1 ]
[ 570391-20-7 ]

Reference： [1] Patent: US2008/280891, 2008, A1,
[2] Patent: WO2008/8059, 2008, A1,

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Yield	Reaction Conditions	Operation in experiment
93%	With sulfuric acid; sodium nitrite; In ethanol; for 3.25h;Heating / reflux;	To a suspension of 2,6-dibromo-4-nitroaniline (75.0 g, 254 mmol) in ethanol (1 L) was added H2SO4 (100 mL). The mixture was heated to reflux and sodium nitrite (50.5 g, 730 mmol) was added portion-wise over a period of 15 min. The mixture was heated at reflux for 3 h and was then cooled to room temperature. The formed thick suspension was poured on ice water (1000 mL) upon which more solid precipitated. The solid was filtered and the filter cake washed with water (2×250 mL) and dried in an oven at 20 mbar/30 C. to give 66.2 g (93%) of 1,3-dibromo-5-nitrobenzene as a brown solid.
93%		Example 11,3-Dibromo-5-nitrobenzene(The named compound was synthesized according to Dumont, Bull. Soc. Chim. Bel., 505 (1995). This compound is also commercially available from Karl Industries, Aurora, Ohio.) To a suspension of 2,6-dibromo-4-nitroaniline (75.0 g, 254 mmol) in ethanol (1 L) was added H2SO4 (100 mL). The mixture was heated to reflux and sodium nitrite (50.5 g, 730 mmol) was added portion-wise over a period of 15 min. The mixture was heated at reflux for 3 h and was then cooled to room temperature. The formed thick suspension was poured on ice water (1000 mL) upon which more solid precipitated. The solid was filtered and the filter cake washed with water (2×250 mL) and dried in an oven at 20 mbar/30 C. to give 66.2 g (93%) of 1,3-dibromo-5-nitrobenzene as a brown solid.
93%	With ethanol; sulfuric acid; sodium nitrite; for 3.25h;Heating / reflux;	Soc. CMm. Bel., 505 (1995). This compound is also commercially available from Karl Industries, Aurora, OH.) To a suspension of 2,6-dibromo- 4-nitroaniline (75.0 g, 254 rnmol) in ethanol (1 L) was added H2SO4 (100 mL). The mixture was heated to reflux and sodium nitrite (50.5 g, 730 mmol) was added portion- wise over a period of 15 min. The mixture was heated at reflux for 3 h and was then cooled to room temperature. The formed thick suspension was poured on ice water (1000 mL) upon which more solid precipitated. The solid was filtered and the filter cake washed with water (2x250 mL) and dried in an oven at 20 mbar/30C to give 66.2 g (93%) of l,3-dibromo-5-nitrobenzene as a brown solid.

90%		Step 1. 1,3-Dibromo-5-nitro-benzene.To an ice-cold solution of 2,6-dibromo-4-nitro-aniline (100 g, 0.34 mol) in 1.50 L of ethanol was added dropwise cone. H2SO4 (116 ml, 2.15 mol) over 30-45 min with constant stirring. The reaction mixture was heated to 600C and sodium nitrite (72 g, 1.09 mol) was added to the reaction mixture portion wise. The resulting yellow colored reaction mixture was heated slowly to 900C and refluxed for 2 to 2.5 h. After cooling to room temperature, the mixture was poured into ice water. The reddish brown solid thus obtained was filtered, washed with water and dried to give the desired compound as a brown solid (85.0 g, 90%). 1H-NMR (400 MHz, DMSOd6): delta 8.38 (d, J= 1.20 Hz, 1 H) and 8.40 Hz1 br s, 2H).
79%	With sulfuric acid; sodium nitrite; In ethanol; at 90℃; for 36h;	In a round bottom flask 2,6-dibromo-4-nitroaniline (29.0 g, 97.73 mmol) were dissolved in 300 mL of ethanol and 35 mL sulfuric acid (conc.). The solution was heated to 90 C. To the solution NaNO2 (21.8 g, 316.1 mmol, 3.23 eq.) was added in small portions and then heated for additional 36 h. The cooled solution was added to ice water. The resulting solid crude product was filtered and washed with water. After recrystallization in ethanol the product was filtered, washed with small portions of ethanol and dried in vacuum overnight (Yield: 21.6 g, 79%). 1H-NMR (CDCl3, 500 MHz): delta (in ppm): 7.98 (t, 4J1,3 = 1.5 Hz, 1 H, 1-H), 8.31 (d, 4J3,1 = 1.5 Hz, 2 H, 3-H). 13C-NMR (CDCl3, 125 MHz): delta (in ppm): 123.43 (Cq, C-2), 125.58 (CH, C-3), 140.03 (CH, C-1), 148.89 (Cq, C-4).
47%	With sulfuric acid; sodium nitrite; In ethanol; at 90℃; for 30h;	1,3-dibromo-5-nitrobenzene (30) To a stirred, boiling (90 C.) mixture of 2,6-dibromo-4-nitroaniline (1 g, 3.38 mmol), ethanol (12 mL) and concentrated sulfuric acid (2 mL), sodium nitrite (0.75 g, 10.88 mmol) was added in portions as rapidly as foaming would permit. The reaction mixture was stirred at 90 C. for 30 h. The mixture was allowed to cool, poured into ice water and the solids were collected by filtration and washed with water. The 3,5-dibromobenzene was separated from the remaining inorganic salts by dissolving it in boiling ethanol and filtering the hot solution, from which 0.457 g (47% yield) of the product (30) crystallized on cooling: 1H-NMR (400 MHz, CDCl3) delta 8.32 (d, J=1.6 Hz, 2H), 8.00 (t, J=1.6 Hz, 1H).
41%	With sulfuric acid; sodium nitrite; In water; ethyl acetate; at 50 - 55℃; for 0.166667h;	Step B: 3,5-Dibromonitrobenzene; NaN02 (4.1 g, 59.1 mmol) was added portionwise to a solution of 2,6-dibromo- 4-nitroaniline (5 g, 3.5eq) in 20% H2S04 and AcOEt (each 40 mL) at a rate to keep the internal temperature at 50-55^. After heating for an additional 10 min, the mixture was cooled, diluted, and extracted with AcOEt . The combined organic layers were dried over Na2S04, filtered and evaporated. The residue was purified by flash chromatography (cyclohexane/ DCM//7/3 then 8/2) to yield expected compound as a white solid (1 .94 g, 41 % yield).H NMR (300 MHz, CDCI3) 5 8.32 (d, J = 1 .8 Hz, 2H), 8.00 (t, J = 1 .8 Hz, 1 H).
2.23 g	With isopentyl nitrite; In N,N-dimethyl-formamide; at 50℃; for 0.166667h;	To a solution of 4-nitroaniline 2g (14.5 mmol, 1eq) in 30 mL of AcOH was added dropwise 1,62 mL (31.9 mmol, 2.2 eq) of bromine and the resulting mixture was stirred at 50 oC overnight. The resulting precipitate was filtered by suction on a glass frit, washed with H2O and dry under vacuum. The solid was then added by portion to a hot (50 oC) stirred solution of isoamyle nitrite 10 mL in 10 mL of DMF. After 10 min the mixture was cooled to room temperature and poured into 100 mL of HCl 3N, subject to extraction with AcOEt (3 X 40 mL), dry over Na2SO4 and concentrated on a rotary evaporator. Purification of the residue by column chromatography yielded 2.23g (55 %) 9b as a yellow solid.1H NMR (CDCl3), d = 8.00 (s, 1H, CHAr); 8.30 (s, 2H, CHAr). 13C NMR (CDCl3), d = 123.8 (2C, Cq); 125.9 (2C, CHAr); 140.5 (1C, CHAr); 149.3 (1C, Cq).

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 2,6-dibromo-4-nitroaniline With hydrogen bromide; sodium nitrite In water at 0℃; for 2h; Stage #2: With urea for 0.333333h; Stage #3: With hydrogen bromide; copper(I) bromide at 0℃; for 2.25h;
	With nitric acid Diazotization_.Faellen mit Brom-Bromkalium in Bromwasserstoffsaeure und Kochen des Reaktionsprodukts mit Alkohol;
	With hydrogen bromide Behandeln mit Natriumnitrit;

	Diazotization_.Umsetzen mit Cuprobromid;
	With potassium disulphite; nitric acid Behandlung des Reaktionsgemisches mit wss. Brom-KBr-Loesung und Kochen des entstandenen Perbromids mit Aethanol;
	Multi-step reaction with 3 steps 1: 97 percent / i-pentyl nitrite; HOAc / 0 - 5 °C 2: 94 percent / aq. NaOH / 0.5 h / 0 - 5 °C 3: 94 percent / aq. HBr / acetonitrile / 2 h / 60 °C
	With tert.-butylnitrite; copper(ll) bromide In acetonitrile

[ CAS No. 827-94-1 ]

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[ 827-94-1 ] Synthesis Path-Upstream 1~10

[ 827-94-1 ] Synthesis Path-Downstream 1~42

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Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 2,6-dibromo-4-nitroaniline With sulfuric acid; sodium nitrite In acetic acid at 20℃; for 4h; Stage #2: With iodine; potassium iodide In water; acetic acid at 20℃; for 12h;
	With nitrosylsulfuric acid; sulfuric acid Diazotization_.Behandlung der Diazoniumsalz-Loesung mit KI in Wasser;
	ueber die Diazoverbindung;

	With sulfuric acid; acetic acid Diazotization_.Behandlung der Diazoniumsalz-Loesung mit KI in Wasser;
	Multi-step reaction with 3 steps 1: 97 percent / i-pentyl nitrite; HOAc / 0 - 5 °C 2: 94 percent / aq. NaOH / 0.5 h / 0 - 5 °C 3: 79 percent / aq. HI / acetonitrile / 13 h / 60 °C

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: 2,6-dibromo-4-nitroaniline With tin(ll) chloride In tetrahydrofuran; ethanol at 50℃; for 16h; Inert atmosphere; Stage #2: With sodium hydroxide In tetrahydrofuran; ethanol at 25℃; for 2.5h; Inert atmosphere;
95%	With hydrazine hydrate In ethanol for 2h; Heating;
80%	With iron; acetic acid at 20℃; Inert atmosphere;

	With hydrogenchloride; tin(ll) chloride
	With hydrogenchloride; tin(ll) chloride
	Stage #1: 2,6-dibromo-4-nitroaniline With sodium tetrahydroborate In methanol for 0.0166667h; Stage #2: With CoCu_0.2Fe_1.8O₄ In methanol for 0.0333333h;
	In <i>N</i>-methyl-acetamide; ethanol; dichloromethane; ethyl acetate	XI 4-Amino-2,6-dibromoaniline EXAMPLE XI 4-Amino-2,6-dibromoaniline 20 g of 2,6-Dibromo-4-nitroaniline are taken up in 250 ml of ethanol, 250 ml of ethyl acetate, 100 ml of dimethylformamide and 90 ml of methylene chloride and, after addition of 3.3 g of 5% moist platinum/active carbon catalyst, hydrogenated at room temperature under 50 psi for one hour. The solvent is then distilled off in a rotary evaporator, and the residue is triturated with diethyl ether, filtered off with suction and washed several times with petroleum ether. Yield: 8 g (45% of theory),; Melting point: 127°-132° C.; Rf: 0.59 (silica gel; petroleum ether/ethyl acetate=10:5)
	With hydrogen In <i>N</i>-methyl-acetamide; ethanol; ethyl acetate	XVIII 1,4-Diamino-2,6-dibromobenzene EXAMPLE XVIII 1,4-Diamino-2,6-dibromobenzene 3.0 g of 2,6-dibromo-4-nitroaniline are dissolved in 150 ml of ethanol, 150 ml of ethyl acetate and 30 ml of dimethylformamide and, after addition of 0.5 g of platinum on carbon (5%), hydrogenated under a pressure of 1.5 bar of hydrogen in a Parr apparatus at room temperature for 1 hour. Cooling is followed by filtration, the solvent is distilled off in a rotary evaporator, and the residue is purified by column chromatography. Yield: 14 g of a colourless oil, Rf: 0.47 (silica gel; petroleum ether/ethyl acetate 2:1).

Yield	Reaction Conditions	Operation in experiment
87%	With bromine In tetrachloromethane at 20℃; Cooling with ice;
	With bromine; acetic acid

Yield	Reaction Conditions	Operation in experiment
98%	With bromine In acetic acid
98%	With N-Bromosuccinimide; lithium perchlorate; silica gel In dichloromethane at 20℃; for 0.0833333h;
98.7%	With hydrogenchloride; brominating reagent In dichloromethane; water at 28℃; for 0.75 - 1h;	5 EXAMPLE 5 To 5.0 ml of dichloromethane containing 4-nitroaniline (1 g, 7.246 m mole) in a 250 ml round bottom flask, 1.45 ml of 12 N hydrochloric acid and 10 ml of deionised water were added. To this reaction mixture, brominating reagent containing (2.9 g) of brominating reagent dissolved in 20 ml of deionised water was added slowly under continuous stirring at 28° C. for a period of 30 to 45 minutes. After completion of the addition, stirring was continued for another 15 minutes. The organic layer was separated and extracted with dichloromethane. The organic layer and the organic extracts were mixed and then washed successively with sodium thiosulphate solution and brine. The product, 2,6-dibromo-4-nitroaniline was dried over anhydrous sodium sulphate and concentrated to yield 98.7%. It was characterized by melting point; NMR; IR and elemental analysis. _

98%	With bromine; calcium bromide In water at 25℃; for 0.333333h; regioselective reaction;
98%	Stage #1: 4-nitro-aniline With acetic acid at 65℃; for 0.75h; Stage #2: With bromine for 1.25h;
97%	With bromine In acetic acid at 65℃; for 4h;
95%	With hydrogen bromide; dihydrogen peroxide In methanol at 0 - 20℃; for 10h;
95%	With hydrogen bromide; dihydrogen peroxide In water at 20℃; for 28h; Darkness;
95%	Stage #1: 4-nitro-aniline With sulfuric acid In water for 0.0833333h; Green chemistry; Stage #2: With sodium bromate; sodium bromide In water at 20℃; for 4h; Green chemistry;
95%	With N-Bromosuccinimide In acetonitrile at 20℃; for 6h;
93%	With PyHBrCl₂ In methanol at 20℃; for 0.0833333h;
93%	With hydrogenchloride; dihydrogen peroxide; sodium bromide In water at 15℃; for 2h;
93%	With bromine In methanol; dichloromethane at 20℃; for 2h;
92%	With bromine; acetic acid at 65℃; for 4h;
92%	With bromine In water at 20℃; for 0.166667h;
91%	With methanol; P-benzyltriphenylphosphonium tribromide; sodium hydrogencarbonate In dichloromethane for 0.25h; Ambient temperature;
90%	With iodine pentoxide; potassium bromide In water at 20℃; for 23h; regioselective reaction;	Typical Procedure for the Bromination of Aromatic CompoundsUsing I₂O₅-KBr in Water General procedure: A mixture of arene (0.5 mmol), I2O5 (334 mg, 1.0 mmol), and KBr (148 mg, 1.25 mmol) was dissolved in 2mL of H2O. The reaction was complete after stirring for the indicated time at room temperature. The mixture was extracted by ethyl acetate and concentrated under reduced pressure, and the mixture was purified by flash column chromatography (silica gel) to afford the desired product.
90%	With dibromamine-T In acetonitrile at 20℃; for 0.166667h;	2, 6-Dibromo-4-nitroaniline General procedure: TsNBr2 (1 mmol) was added at 0 C to a solution of the aromatic compound(1 mmol) in acetonitrile (2 mL). After 10 min of stirring at room temperature, sodium thiosulfate (200 mg approx.) was added and stirred for 10 min. The reaction wastaken up in ethyl acetate, dried over NaSO4, and concentrated. The crude productwas purified by flash chromatography or silica gel (230-400 mesh) with a mixtureof petroleum ether and ethyl acetate as eluent.
89%	With bromine
85.2%	With bis<dimethylacetamide>hydrogen dibromobromate In ethanol; water
85%	With 1-benzyl-1-aza-4-azoniabicyclo<2.2.2>octane bromide; calcium carbonate In methanol at 20℃; for 0.666667h;
	With bromine
	With hydrogenchloride; bromine
	With sulfuric acid; bromine
	With methanol; bromine
	With bromine; acetic acid
	With bromine; acetic acid
	With bromine; acetic acid for 4h;
	With bromine In hydrogenchloride; acetic acid for 3h;
	Multi-step reaction with 2 steps 1: bromine / tetrachloromethane / 4 h / 10 - 20 °C 2: bromine / tetrachloromethane / 20 °C / Cooling with ice
	With bromine In acetic acid at 50℃;	3,5-dibromonitrobenzene 9b To a solution of 4-nitroaniline 2g (14.5 mmol, 1eq) in 30 mL of AcOH was added dropwise 1,62 mL (31.9 mmol, 2.2 eq) of bromine and the resulting mixture was stirred at 50 oC overnight. The resulting precipitate was filtered by suction on a glass frit, washed with H2O and dry under vacuum. The solid was then added by portion to a hot (50 oC) stirred solution of isoamyle nitrite 10 mL in 10 mL of DMF. After 10 min the mixture was cooled to room temperature and poured into 100 mL of HCl 3N, subject to extraction with AcOEt (3 X 40 mL), dry over Na2SO4 and concentrated on a rotary evaporator. Purification of the residue by column chromatography yielded 2.23g (55 %) 9b as a yellow solid.1H NMR (CDCl3), d = 8.00 (s, 1H, CHAr); 8.30 (s, 2H, CHAr). 13C NMR (CDCl3), d = 123.8 (2C, Cq); 125.9 (2C, CHAr); 140.5 (1C, CHAr); 149.3 (1C, Cq).
	With bromine; acetic acid
90 %Chromat.	With Oxone; ammonium bromide In methanol; water at 20℃; for 0.0833333h; Green chemistry; regioselective reaction;
	With bromine; acetic acid

Yield	Reaction Conditions	Operation in experiment
95%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,2-dimethoxyethane; ethanol; water for 14h; Heating;
94%	With potassium phosphate tribasic heptahydrate; palladium diacetate In water; N,N-dimethyl-formamide at 80℃; for 1h;
55%	With sodium carbonate In ethanol; benzene for 48h; Heating;

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: NaNO₂; H₂SO₄; aq. H₃PO₄ / 2 h 1.2: urea; H₂SO₄; aq. H₃PO₄ / 20 °C 1.3: 85 percent / H₂SO₄; aq. H₃PO₄ / 0 - 20 °C 2.1: 99 percent / tin; aq. HCl / 7 h / 90 °C
	Multi-step reaction with 2 steps 1: 80 percent / H₂SO₄; NaNO₂ / ethanol / 36 h / 90 °C 2: 89 percent / SnCl₂*2H₂O / ethanol; tetrahydrofuran / 20 h / 20 °C
	Multi-step reaction with 2 steps 1: 97 percent / NaNO₂, H₂SO₄ / ethanol 2: 96 percent / 1.) H₂; 2.) aq. HCl / Raney Ni / ethanol

	Multi-step reaction with 2 steps 1: 94 percent / conc. sulfuric acid, sodium nitrite / ethanol / 3 h / Heating 2: 78 percent / 1.) iron powder, acetic acid, 2.) NaOH / ethanol / 2 h / Heating
	Multi-step reaction with 2 steps 2: tin; hydrochloric acid
	Multi-step reaction with 2 steps 2: iron; diluted sulfuric acid
	Stage #1: 2,6-dibromo-4-nitroaniline With sulfuric acid; sodium nitrite In ethanol Stage #2: With water; tin(ll) chloride In ethanol
	Multi-step reaction with 2 steps 1: ethanol; sulfuric acid; sodium nitrite / 3 h / 60 - 90 °C / Cooling with ice; Inert atmosphere 2: tin(II) chloride dihdyrate / ethanol / 1.5 h / 80 °C
	Multi-step reaction with 2 steps 1: sodium nitrite; sulfuric acid / ethanol / 4 h / 80 °C 2: iron; ammonium chloride / water; acetone / 6 h / 80 °C
	Multi-step reaction with 2 steps 1: sulfuric acid; sodium nitrite / ethanol / 90 °C 2: tin(II) chloride dihdyrate / ethanol; tetrahydrofuran / 22 °C
	Multi-step reaction with 2 steps 1.1: sulfuric acid; sodium nitrite / ethanol / 40 h / 80 °C 2.1: tin(II) chloride dihdyrate / methanol; tetrahydrofuran / 20 h / 60 °C 2.2: 2 h
	Multi-step reaction with 2 steps 1.1: sulfuric acid / ethanol / 0.5 - 0.75 h / 0 °C 1.2: 2 - 2.5 h / 60 - 90 °C / Heating / reflux 2.1: tin(ll) chloride / ethanol / 1.5 h / 20 - 80 °C / Heating / reflux 2.2: pH 12

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite In sulfuric acid; hydrogen bromide; acetic acid	2.a a) a) 3,4,5-Tribromonitrobenzene At 20° C., with stirring and cooling with ice, a solution of 2,6-dibromo-4-nitro-aniline (47.2 g) in acetic acid (1.6 liters) is slowly poured into a solution of sodium nitrite (12 g) in concentrated sulphuric acid (85 ml). Then, the mixture is stirred for 20 minutes at ambient temperature. The solution thus prepared is then slowly added with stirring and cooling with ice to a solution of copper (I) bromide (12.8 g) in 63% hydrobromic acid (40 ml). After it has all been added the mixture is stirred for a further 30 minutes. It is diluted with water, the precipitate is filtered off and washed with water. This crude product is recrystallized from methanol. Colorless crystals, m.p. 110° C.
	With sodium nitrite In sulfuric acid; hydrogen bromide; acetic acid	2.a (a) (a) 3,4,5-Tribromonitrobenzene At 20° C., with stirring and cooling with ice, a solution of 2,6-dibromo-4-nitro-aniline (47.2 g) in acetic acid (1.6 liters) is slowly poured into a solution of sodium nitrite (12 g) in concentrated sulphuric acid (85 ml). Then, the mixture is stirred for 20 minutes at ambient temperature. The solution thus prepared is then slowly added with stirring and cooling with ice to a solution of copper (I) bromide (12.8 g) in 63% hydrobromic acid (40 ml)/. After it has all been added the mixture is stirred for a further 30 minutes. It is diluted with water, the precipitate is filtered off and washed with water. This crude product is recrystallized from methanol. Colorless crystals, m.p. 110° C.

Yield	Reaction Conditions	Operation in experiment
1: 84% 2: 13%	With dihydrogen peroxide; potassium bromide In water; acetonitrile
	With N-Bromosuccinimide In water at 20℃; for 8h;
1: 98 %Chromat. 2: 2 %Chromat.	With sodium persulfate; copper(ll) sulfate pentahydrate; sodium bromide In water; acetonitrile at 7 - 25℃; for 24h; Overall yield = 98 percent; Overall yield = 1.5 g; regioselective reaction;	4-Bromo-2-nitroaniline (2a); Typical Procedure for Bromination General procedure: 2-Nitroaniline (1.0 g, 7.24 mmol) was added to a suspension of CuSO4·5H2O (0.452 g, 1.81 mmol, 25 mol%) in a mixture of CH3CN (20mL) and H2O (10 mL) at 25 °C, and the mixture was stirred at 25 °C for15 min. NaBr (1.34 g, 13.0 mmol, 1.8 equiv.) and Na2S2O8 (2.41 g, 10.1mmol, 1.4 equiv.) were then added simultaneously in three portionsat 7 °C over 15 min. After addition was complete, the mixture was furtherstirred at 7 °C for 2 h and at 25 °C for 22 h. Na2S2O3 (572 mg, 3.62 mmol) was added to the mixture. The pH value of the mixture wasthen adjusted to 9.0 by adding 10% aq. NaOH (8 mL). The mixture wasdiluted with H2O (100 mL) and extracted with AcOEt (100 mL). Theorganic phase was separated and subjected to HPLC analysis (X BridgeC18, 5 m, 4.6 × 150 mm, 30 °C, 1 mL min-1, 50-90% CH3CN (0-20min) then 50% (20-40 min), 254 nm) to obtain the assay yield of 2a(1.49 g, 94.9%) and the ratio of 2a/3a (99.9:0.1). Pure samples of 2aand 3a for analysis were obtained by purification of the evaporatedmixture with silica gel column chromatography (n-hexane/AcOEt =15:1).

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 5h;
8.08 g	With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 5h;	10 The preparation of compound B-115 3.12g (0.078 mol) of sodium hydroxide was added to a solution of 8.07g(0.039 mol) of 2,6-dichloro-4-nitroanilinein 60 mL of DMF, followed by addition of 7.80g (0.039 mol) of 2,4,5,6-tetrafluoroisophthalonitrile under stirring, the mixturewas stirred for 5 h after addition at room temperature. After the reaction was over by Thin-Layer Chromatographymonitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washedwith water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reducedpressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling point range 60-90°C)= 1:5, as an eluent) to give 8.08 g of compound B-115 as yellowish solid, m.p. 164-166°C.[0096] 1H-NMR (300MHz, internal standard TMS, solvent CDCl3) δ(ppm): 6.88(br, 1H, NH), 8.53(s, 2H, Ph-3,5-2H).

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,6-dibromo-4-nitroaniline With naphthalene-1,5-disulfonate In ethyl acetate at 50℃; for 0.166667h; Stage #2: With tert.-butylnitrite In ethyl acetate at 25℃; for 0.333333h; Stage #3: N-ethyl-N-(2-cyanoethyl)aniline With hydrogenchloride In water at 0 - 5℃; for 0.2h;	2.4 Typical procedure for coupling General procedure: N,N-Diethylaniline (10mmol) was dissolved in 80mL water with 1.2mL 37% hydrochloric acid and then the salmon pink diazonium salt of 2,4-dinitroaniline was quickly added within 2minat 0°C-5°C followed by adjusting the pH to 4-5 with 2M NaOH solution. The reaction endpoint was confirmed by color reaction using H-acid. The precipitated dye was filtered, washed with water and dried at 80°C to afford the crude product. The crude yield was 95.0% and the degree of purity was 97.0%.
	Stage #1: 2,6-dibromo-4-nitroaniline With nitrosylsulfuric acid; sulfuric acid at 5 - 40℃; for 5h; Stage #2: N-ethyl-N-(2-cyanoethyl)aniline With urea at 10 - 80℃; for 5.25h;	Preparation 16 A) adding sulfuric acid to the diazo kettle,Open the diazo kettle stir,And then slowly add nitrosyl sulfuric acid,Control the temperature does not exceed 40 ,Plus finished, cooling to 25 ,The intermediate 2,6-dibromo-4-nitroaniline was added slowly,Plus 5 ~ 30 in the incubation reaction 5 hours,To obtain a diazo component, stand-by;B) adding water to the diazo dilution kettle,Ice, cool to below 5 ,Pressed into the above-mentioned diazonium solution for dilution,Control the dilution temperature below 5 ,Pressure, add activated carbon,Stir for 60 minutes, filter,The diazo filtrate into the coupling kettle.C) Diazo filtrate is completed,Open the coupling kettle stir,Ice was added urea and peregal,Stir for 15 minutes,Adding isooctanol,Control the temperature below 10 ,The addition of the coupling component N-ethyl-N-cyanoethylaniline,Dropping time 3 hours, plus finished,Control temperature 10 ~ 15 incubation reaction 2 hours,Slowly warming to 80 turn crystal,Filtered and washed with water to give the product (III-1).
1600 kg	Stage #1: 2,6-dibromo-4-nitroaniline With nitrosylsulfuric acid; sulfuric acid at 15 - 25℃; for 5h; Industrial scale; Stage #2: N-ethyl-N-(2-cyanoethyl)aniline With aminosulfonic acid at -3 - 60℃; for 5h; Industrial scale;	1 Example 1: 98% 500kg sulfuric acid, 40% 1094kg nitrosylsulfuric acid were added to the reaction vessel, cold saline spaced jacket temperature was controlled at 15-25 °C. 93% of 2,6-dibromo-4-nitro aniline 1075.3kg was slowly added. After the addition was complete, the reaction was kept for 5h, to be coupled with the diazonium salt. In the coupling kettle, 5 kg of sulfamic acid, OP-105kg of additive, 587kg (N-ethyl-N-cyanoethylaniline) of 98% coupling component, 7000kg of crushed ice. The diazonium salt was added dropwise under stirring, and the addition time was 2 h. After the completion of the dropwise addition, the ice was kept at a temperature of -3 °C for 2 hours, and then heated to 60 °C with steam for 1 h. The material is pumped into the filter press, washed at 50 °C hot water, and the filter cake is dried 1600 kg, HPLC is 98%.

Yield	Reaction Conditions	Operation in experiment
90.45%	Stage #1: 2,6-dibromo-4-nitroaniline With tert.-butylnitrite; naphthalene-1,5-disulfonate In 1,2-dimethoxyethane at 20℃; for 1h; Stage #2: m-acetylamino-N,N-diethylanilne With sodium carbonate; naphthalene-1,5-disulfonate In water at 0℃; for 0.166667h;	4 Preparation of N,N-diethyl-4-(2,6-dibromo-4-nitrophenylazo)-3-acetamidoaniline dye Diazotization reaction: 2.96 g of 2,6-dibromo-4-nitroaniline was dissolved in 60 mL of ethylene glycol dimethyl ether, To a solution of 2,6-dibromo-4-nitroaniline was added 4.32 g of 1,5-naphthalenedisulfonic acid, 1.72 g of t-butyl nitrite was added with stirring at 20 °C, reacted at 20 ° C for 1 h, Get diazonium salt; Coupling reaction: 2.06 g of N,N-diethyl-3-acetamidoaniline was dissolved in 2.88 g of 1,5-naphthalenedisulfonic acid 100 mL of water was added at 0 °C to a diazonium salt obtained by the diazotization reaction step, With anhydrous sodium carbonate to adjust the pH to 4~6, 0 °C reaction 10min, adjust the pH to neutral, filter, wash,Dried to give N,N-diethyl-4-(2,6-dibromo-4-nitrophenylazo)-3-acetylaminoaniline dye in a yield of 90.45%.
	Stage #1: 2,6-dibromo-4-nitroaniline With naphthalene-1,5-disulfonate In ethyl acetate at 50℃; for 0.166667h; Stage #2: With tert.-butylnitrite In ethyl acetate at 25℃; for 0.333333h; Stage #3: m-acetylamino-N,N-diethylanilne With hydrogenchloride In water at 0 - 5℃; for 0.1h;	2.4 Typical procedure for coupling General procedure: N,N-Diethylaniline (10mmol) was dissolved in 80mL water with 1.2mL 37% hydrochloric acid and then the salmon pink diazonium salt of 2,4-dinitroaniline was quickly added within 2minat 0°C-5°C followed by adjusting the pH to 4-5 with 2M NaOH solution. The reaction endpoint was confirmed by color reaction using H-acid. The precipitated dye was filtered, washed with water and dried at 80°C to afford the crude product. The crude yield was 95.0% and the degree of purity was 97.0%.

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
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P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
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P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
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P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling