[ CAS No. 84487-04-7 ] {[proInfo.proName]}

Name: 84487-04-7|2-Amino-6-bromo-3-nitropyridine|95%
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SKU: A811389
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Quality Control of [ 84487-04-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 84487-04-7 ]

CAS No. :	84487-04-7	MDL No. :	MFCD07774108
Formula :	C₅H₄BrN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YRXZIHANXVKUHP-UHFFFAOYSA-N
M.W :	218.01	Pubchem ID :	12097745
Synonyms :

Calculated chemistry of [ 84487-04-7 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.16
TPSA :	84.73 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) :	-6.27 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.11
Log Po/w (XLOGP3) :	1.91
Log Po/w (WLOGP) :	1.34
Log Po/w (MLOGP) :	-0.11
Log Po/w (SILICOS-IT) :	-0.73
Consensus Log Po/w :	0.7

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.73
Solubility :	0.404 mg/ml ; 0.00185 mol/l
Class :	Soluble
Log S (Ali) :	-3.31
Solubility :	0.106 mg/ml ; 0.000487 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.91
Solubility :	2.71 mg/ml ; 0.0124 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.42

Safety of [ 84487-04-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H302-H312-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 84487-04-7 ]

* 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 [ 84487-04-7 ]
Downstream synthetic route of [ 84487-04-7 ]

[ 84487-04-7 ] Synthesis Path-Upstream 1~7

1
[ 84487-04-7 ]
[ 129012-04-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With acetic acid; zinc In methanol; ethanol at 0 - 20℃; for 15 h;	Step 1: To a stirred mixture of 6-bromo-3-nitro-2-pyridinamine (2.5 g, 11.47 mmol) in a mixture of glacial HOAc(10 mL), MeOH (10 mL) and EtOH (10 mL) at 0 °C was added portionwise zinc dust (3.73 g, 57.35 mmol). The mixturewas stirred at rt for 15 h. The mixture was filtered through Celite, and the filtrate was concentrated under reducedpressure. The residue was partitioned between saturated aq NaHO3 and EtOAc. The organic layer was separated andthe aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, separatedand dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-bromopyridine-2,3-diamine (1.30g, 60percent) as a solid that did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 6.61 (d, J = 7.7 Hz, 1H), 6.47(d, J = 7.7 Hz, 1H), 5.82 (s, 2H), 4.79 (s, 2H). LCMS (ESI) m/z 188 and 190 (M+H)+.

Reference： [1] Patent: EP2766359, 2016, B1, . Location in patent: Paragraph 0578
[2] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 91
[3] Patent: US2014/315888, 2014, A1, . Location in patent: Paragraph 1221-1222
[4] Patent: US6348474, 2002, B1, . Location in patent: Page column 45

2
[ 7439-89-6 ]
[ 84487-04-7 ]
[ 129012-04-0 ]

Reference： [1] Patent: US6573274, 2003, B1,

3
[ 27048-04-0 ]
[ 84487-04-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With hydrogen bromide In water; acetic acid at 100℃; for 26 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	To a solution of commercially available 2,6-dichloro-5- nitropyridine (20.0 g, 95.3 mmol) in ethanol (300 mL) was added aqueous ammonia (60 mL), and the mixture was stirred at room temperature for 10 hours. The resulting precipitate was filtered, washed with ethanol, and dried in vacuo to give 6-amino-2-chloro-5-nitropyridine (13. [8 G, 83 percent). THE COMPOUND] thus obtained was suspended in an acetic acid solution (130 mL) of [30percent] hydrogen bromide. The suspension was stirred at [100°C] for 26 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue thus obtained [ WAS RECRYSTALLIZED FROM ETHYL ACETATE TO GIVE THE TITLE COMPOUND] (14.93 g, 86 [percent).]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5702 - 5713
[2] Patent: WO2004/2986, 2004, A2, . Location in patent: Page 127-128
[3] Patent: US6348474, 2002, B1, . Location in patent: Page column 44,45

4
[ 55304-80-8 ]
[ 84487-04-7 ]

Reference： [1] Patent: US2014/315888, 2014, A1, . Location in patent: Paragraph 1219-1220
[2] Patent: US6348474, 2002, B1, . Location in patent: Page column 136

5
[ 1643-19-2 ]
[ 73896-36-3 ]
[ 84487-04-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With phosphorus pentaoxide; hydrogen bromide; acetic acid In toluene	B. 6-Bromo-3-nitro-pyridin-2-ylamine. To a glass pressure vessel containing 6-methoxy-3-nitro-pyridin-2-ylamine (5.0 g, 29.5 mmol) was added 30percent hydrogen bromide/acetic acid (60 mL). The vessel was sealed, and the contents were heated to 60° C. for 24 h. The reaction mixture was cooled, and the solvent was removed in vacuo giving 6.8 g (>95percent) of crude 6-amino-5-nitro-pyridin-2-ol hydrobromide (HPLC: R_t=5.46). This material (2.0 g, 8.5 mmol) was taken up in toluene (30 mL), followed by phosphorus pentoxide (2.4 g, 17.0 mmol) and tetrabutyl ammonium bromide (3.2 g, 9.7 mmol). The mixture was heated to reflux for 4 h. The reaction mixture was cooled to ⁰° C., diluted with saturated NaHCO₃, and extracted with ethyl acetate (3*100 mL). The combined organics were washed with water (100 mL) and dried (Na₂SO₄) to afford 1.18 g (64percent) of 6-bromo-3-nitro-pyridin-2-ylamine. HPLC: R_t=8.17. ¹H NMR (400 MHz, DMSO-d₆): 8.33 (br s, 2H), 8.32 (d, J=8.6 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H).

Reference： [1] Patent: US2003/176438, 2003, A1,

6
[ 55304-80-8 ]
[ 84487-04-7 ]

Reference： [1] Patent: US6573274, 2003, B1,

7
[ 84487-04-7 ]
[ 219762-28-4 ]

Reference： [1] Patent: US6573274, 2003, B1,
[2] Patent: US6348474, 2002, B1,
[3] Patent: US6348474, 2002, B1,

[ 84487-04-7 ] Synthesis Path-Downstream 1~88

1
[ 84487-04-7 ]
[ 538372-33-7 ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 5707 - 5716

2
[ 84487-04-7 ]
2-(1-methyl-4-nitro-1H-pyrrol-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 5707 - 5716

3
[ 84487-04-7 ]
5-amino-6-[(1-methyl-4-nitro-1H-pyrrole-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 5707 - 5716
[2]Journal of the American Chemical Society,2003,vol. 125,p. 5707 - 5716

4
[ 84487-04-7 ]
6-amino-5-[(1-methyl-4-nitro-1H-pyrrole-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 5707 - 5716

5
[ 84487-04-7 ]
[ 538372-35-9 ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 5707 - 5716

6
[ 84487-04-7 ]
[ 538372-36-0 ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 5707 - 5716

7
[ 108-24-7 ]
[ 84487-04-7 ]
[ 219766-89-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In acetic acid; at 65℃; for 0.666667h;	Preparation Example 106-2 2-(Acetamido)-6-bromo-3-nitropyridine To a suspension of 2-amino-6-bromo-3-nitropyridine (23.9 g) in acetic acid (48 ml) were added acetic anhydride (48 ml) and sulfuric acid (2.9 ml), and the mixture was heated at 65 C. for 40 min.. The mixture was uniform so that it quickly became a suspension containing a precipitate.. After cooling, the reaction mixture was poured into cold water (480 ml) and the mixture was stirred for 30 min.. The precipitate was collected by filtration and washed with water to give a crude product.. The crude product was suspended in ether (60 ml) and collected by filtration to give the objective compound (27.2 g) as a pale-yellow powder. 1H-NMR(CDCl3): 2.54(3H, s), 7.33(1H, d, J=8 Hz), 8.33(1H, d, J=8 Hz), 9.95(1H, br s).

Reference： [1]Patent: US6348474,2002,B1 .Location in patent: Page column 136

8
[ 84487-04-7 ]
[ 129012-04-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With acetic acid; zinc; In methanol; ethanol; at 0 - 20℃; for 15h;	Step 1: To a stirred mixture of 6-bromo-3-nitro-2-pyridinamine (2.5 g, 11.47 mmol) in a mixture of glacial HOAc(10 mL), MeOH (10 mL) and EtOH (10 mL) at 0 C was added portionwise zinc dust (3.73 g, 57.35 mmol). The mixturewas stirred at rt for 15 h. The mixture was filtered through Celite, and the filtrate was concentrated under reducedpressure. The residue was partitioned between saturated aq NaHO3 and EtOAc. The organic layer was separated andthe aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, separatedand dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-bromopyridine-2,3-diamine (1.30g, 60%) as a solid that did not require further purification. 1H NMR (300 MHz, DMSO-d6) delta 6.61 (d, J = 7.7 Hz, 1H), 6.47(d, J = 7.7 Hz, 1H), 5.82 (s, 2H), 4.79 (s, 2H). LCMS (ESI) m/z 188 and 190 (M+H)+.
	With tin(II) chloride dihdyrate; In N,N-dimethyl-formamide; at 80℃; for 2h;	To a DMF solution (40 mL) containing 2-amino-6-bromo-3-nitropyridine (2.43 g, 11.1 mmol, as described in WO2004002986) was added SnCl2.2H2O (10.0 g, 44.4 mmol). The solution was then heated to 80 degrees C. for 2 hr. Upon cooling the solution was made basic with 1 N NaOH. The organics were extracted with EtOAc (4×) followed by drying over MgSO4. The solvent was removed in vacuo and the residue purified on the Biotage (70-90% EtOAc/hexanes) yielding 1.26 g (6.69 mmol) of 6-bromo-2,3-pyridinediamine. 1H NMR (400 MHz, d6-DMSO) delta 8.6.56 (d, 1H, J=7.7 Hz), 6.42 (d, 1H, J=7.7 Hz), 5.77 (s(br), 2H), 4.74 (s(br), 2H) ppm
	With tin(II) chloride dihdyrate; In N,N-dimethyl-formamide; at 80℃; for 2h;	6-Bromo-3-nitropyridin-2-amine (520.0 mg, 2.39 mmol) and SnCl22H2O (2140.0 mg, 9.54 mmol) were added to DMF (8.6 mL), and the reaction mixture was stirred at 80 C. for 2 hours. The reaction mixture was cooled to room temperature, basified with 1N NaOH (pH=9) and then extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain brown solid compound of 6-bromopyridine-2,3-diamine (238.0 mg, 44%). [1222] 1H-NMR (400 MHz, DMSO-d6); delta: 6.62 (d, 1H, J=8.4 Hz), 6.48 (d, 1H, J=8.4 Hz), 5.81 (brs, 2H), 4.79 (brs, 2H)

With hydrogenchloride; iron; In ethanol; water; at 20℃; for 2h;Heating / reflux;

Preparation Example 9-2 2,3-Diamino-6-bromopyridine To a suspension of 2-amino-6-bromo-3-nitropyridine (21.8 g) in ethanol (220 ml) in water (22 ml) was added iron powder (39.0 g) at room temperature.. concentrated hydrochloric acid (0.8 ml) was added and the mixture was slowly heated with stirring to start the reaction.. The mixture was refluxed under heating for 2 hr and the insoluble matter was filtered off while it was hot.. The solvent was evaporated under reduced pressure and water (200 ml) and active carbon were added to the remaining solid, which was followed by heating.. The insoluble matter was filtered off while it was hot.. water was evaporated under reduced pressure from the filtrate to give the objective compound (9.00 g) as a green-brown powder.. ethanol (100 ml)-water (100 ml) was added to the solid from the above operation and the mixture was heated for dissolution, and the insoluble matter was filtered off.. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatograhy (hexane/ethyl acetate=1/3) to give the objective compound (8.25 g) as a black powder. 1H-NMR(DMSO-d6): 4.78(2H, br s), 5.80(2H, br s), 6.47(1H, d, J=8 Hz), 6.61(1H, d, J=8 Hz) Mass(ESI): m/e 188, 190 (M+H)+

Reference： [1]Patent: EP2766359,2016,B1 .Location in patent: Paragraph 0578
[2]Patent: US2010/222345,2010,A1 .Location in patent: Page/Page column 91
[3]Patent: US2014/315888,2014,A1 .Location in patent: Paragraph 1221-1222
[4]Patent: US6348474,2002,B1 .Location in patent: Page column 45

9
[ 27048-04-0 ]
[ 84487-04-7 ]

Yield	Reaction Conditions	Operation in experiment
86%		To a solution of commercially available 2,6-dichloro-5- nitropyridine (20.0 g, 95.3 mmol) in ethanol (300 mL) was added aqueous ammonia (60 mL), and the mixture was stirred at room temperature for 10 hours. The resulting precipitate was filtered, washed with ethanol, and dried in vacuo to give <strong>[27048-04-0]6-amino-2-chloro-5-nitropyridine</strong> (13. [8 G, 83 %). THE COMPOUND] thus obtained was suspended in an acetic acid solution (130 mL) of [30%] hydrogen bromide. The suspension was stirred at [100C] for 26 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue thus obtained [ WAS RECRYSTALLIZED FROM ETHYL ACETATE TO GIVE THE TITLE COMPOUND] (14.93 g, 86 [%).]
	With hydrogen bromide; In acetic acid; at 20 - 100℃; for 72h;	Preparation Example 9-1 2-Amino-6-bromo-3-nitropyridine A 30% solution of hydrogen bromide in acetic acid (10 ml) was added to <strong>[27048-04-0]2-amino-6-chloro-3-nitropyridine</strong> (1.0 g) at room temperature and the mixture was heated at 100 C. After 24 hr, a 30% solution of hydrogen bromide in acetic acid (5 ml) was added.. After 48 hr, the reaction mixture was cooled and concentrated.. The residue was neutralized with 28% aqueous ammonia and extracted three times with ethyl acetate.. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated.. The residue was crystallized from isopropyl ether to give the objective compound (1.14 g) as yellow crystals. 1H-NMR(DMSO-d6): 6.90(1H, d, J=8 Hz), 8.25(1H, d, J=8 Hz) MASS(ESI): m/z 217(M-1)

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5702 - 5713
[2]Patent: WO2004/2986,2004,A2 .Location in patent: Page 127-128
[3]Patent: US6348474,2002,B1 .Location in patent: Page column 44,45

10
[ 55304-80-8 ]
[ 84487-04-7 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In ethanol; at 20℃; for 12h;	2,6-Dibromo-3-nitropyridine (700.0 mg, 2.48 mmol) was added to 2M ammonia solution in EtOH (25.0 mL, 49.66 mmol). The mixture stirred at room temperature for 12 hours and concentrated under reduced pressure to obtain yellow solid compound of 6-bromo-3-nitropyridin-2-amine (526.0 mg, 97%). [1220] 1H-NMR (400 MHz, DMSO-d6); delta: 8.26 (m, 3H), 6.91 (d, 1H, J=8.4 Hz)
	With ammonia; In ethanol; at 20℃; for 19h;	Preparation Example 106-1 2-Amino-6-bromo-3-nitropyridine To a suspension of <strong>[55304-80-8]2,6-dibromo-3-nitropyridine</strong> (5.00 g) in ethanol (10 ml) was added an ammonia/ethanol solution (6.8 M, 15 ml) at room temperature, and the mixture was placed in a closed reaction vessel and stirred at room temperature for 19 hr.. To the reaction mixture was added water (25 ml), and the precipitate was collected by filtration.. The precipitate was washed with ethanol, suspended in ethanol (55 ml), heated and cooled.. The precipitate was collected by filtration to give the objective compound (3.19 g) as a yellow powder. 1H-NMR(DMSO-d6): 6.89(1H, d, J=8 Hz), 8.24(1H, d, J=8 Hz), 8.25(2H, br s).

Reference： [1]Patent: US2014/315888,2014,A1 .Location in patent: Paragraph 1219-1220
[2]Patent: US6348474,2002,B1 .Location in patent: Page column 136

11
[ 1993-03-9 ]
[ 84487-04-7 ]
2,3-diamino-6-(2-fluorophenyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a solution of 6-amino-2-bromo-5-nitropyridine (2.0 g, 9.2 mmol) and 2-fluorophenylboronic acid (2.57 g, 18 mmol) in dimethoxyethane (60 mL) were added 2M aqueous sodium carbonate solution (18 mL) and tetrakistriphenylphosphine palladium [(0)] (106 mg, 0.092 mmol). The mixture was stirred at [105C FOR] 16 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate (30 mL) and methanol (30 mL). To the solution was added 10% palladium carbon (200 mg), and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. After removal of the palladium catalyst by filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform: methanol=30: 1) to give the title compound (1.87 g, [100] [%)] as a reddish brown oil. [HNMR] (300 MHz, CD30D, [B] [PPM) :] 6.89-6. 96 (2H, m), 7.06-7. 12 [(1H,] m), 7.15-7. 20 [(1H,] m), 7.25-7. 30 (1H, m), 7.65-7. 70 (1H, m); mass spectrum [(ESI) :] 204 (M+H)

Reference： [1]Patent: WO2004/2986,2004,A2 .Location in patent: Page 128-129

12
[ 13331-23-2 ]
[ 84487-04-7 ]
[ 868360-37-6 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 16h;	To a solution of <strong>[84487-04-7]6-bromo-3-nitropyridin-2-amine</strong> (1.0 g, 4.6 mmol) and 2-furylboronic acid (0.76 g, 6.9 mmol) in dimethoxyethane (30 mL) and water (2 mL), potassium carbonate (0:58 g, 4.23 mmol) was added. The mixture was purged with Argon and then tetrakis(triphenylphosphine)palladium(0) (0.53 g; 0.46 mmol) was added. The mixture was heated at 80 C for 16 hours.. The mixture was then cooled, diluted with ethyl acetate and washed with water, brine, dried (MgS04) and evaporated. The crude mixture was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (0.43 g, 46%). # 1H NMR (CDCI3): 6.57-6.59 (m, 1 H), 7.15-7.19 (m, 2H), 7.61 (s, 1 H), 8.43 (d, 1H). ESI/MS (m/e, %) : 206 [(M+1) +, 100].
42%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 95℃; for 3h;Inert atmosphere;	Synthesis of 198-A. A mixture of <strong>[84487-04-7]6-bromo-3-nitropyridin-2-amine</strong> (5.0 g, 23.0 mmol), furan-2-ylboronic acid (3.1 g, 27.6 mmol) and Cs2CO3 (22.5 g, 69.0 mmol) in dioxane/H2O (100 mL/10 mL) was added Pd(PPh3)4 (2.44g, 2.88 mmol) under N2 atmosphere. The mixture was stirred at 95 oC for 3 h and then concentrated in vacuo. The residue was dissolved with EtOAc (200 mL) and the solution was washed with brine (100 mL × 3). The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10 : 1 ~ 5 : 1) to give 198-A (2.0 g, 42%) as a yellow solid

Reference： [1]Patent: WO2005/100353,2005,A1 .Location in patent: Page/Page column 29-30
[2]Patent: WO2017/7756,2017,A1 .Location in patent: Paragraph 483

13
[ 1643-19-2 ]
[ 73896-36-3 ]
[ 84487-04-7 ]

Yield	Reaction Conditions	Operation in experiment
1.18 g (64%)	With phosphorus pentaoxide; hydrogen bromide; acetic acid; In toluene;	B. 6-Bromo-3-nitro-pyridin-2-ylamine. To a glass pressure vessel containing <strong>[73896-36-3]6-methoxy-3-nitro-pyridin-2-ylamine</strong> (5.0 g, 29.5 mmol) was added 30% hydrogen bromide/acetic acid (60 mL). The vessel was sealed, and the contents were heated to 60 C. for 24 h. The reaction mixture was cooled, and the solvent was removed in vacuo giving 6.8 g (>95%) of crude 6-amino-5-nitro-pyridin-2-ol hydrobromide (HPLC: Rt=5.46). This material (2.0 g, 8.5 mmol) was taken up in toluene (30 mL), followed by phosphorus pentoxide (2.4 g, 17.0 mmol) and tetrabutyl ammonium bromide (3.2 g, 9.7 mmol). The mixture was heated to reflux for 4 h. The reaction mixture was cooled to 0 C., diluted with saturated NaHCO3, and extracted with ethyl acetate (3*100 mL). The combined organics were washed with water (100 mL) and dried (Na2SO4) to afford 1.18 g (64%) of 6-bromo-3-nitro-pyridin-2-ylamine. HPLC: Rt=8.17. 1H NMR (400 MHz, DMSO-d6): 8.33 (br s, 2H), 8.32 (d, J=8.6 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H).

Reference： [1]Patent: US2003/176438,2003,A1

14
[ 84487-04-7 ]
[ 516481-67-7 ]

Yield	Reaction Conditions	Operation in experiment
50 mg (67%)	In dichloromethane; N,N-dimethyl acetamide;	C. 6-Amino-5-nitro-pyridine-2-carbonitrile. To a glass pressure vessel was added <strong>[84487-04-7]6-bromo-3-nitro-pyridin-2-ylamine</strong> (100 mg, 0.46 mmol), copper cyanide (123 mg, 1.38 mmol) and N,N-dimethylacetamide (3.0 mL). The vessel was sealed, and the contents were heated to 120 C. for 24 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The resulting precipitate was collected by filtration and was then stirred with CH2Cl2 (10 mL) for 24 h. The mixture was filtered, and the filtrate was concentrated to afford 50 mg (67%) of 6-amino-5-nitro-pyridine-2-carbonitrile. HPLC: Rt=7.63. 1H NMR (400 MHz, DMSO-d6): 8.68 (d, J=8.4 Hz, 1H), 8.27 (br s, 2H), 7.34 (d, J=8.4 Hz, 1H).

Reference： [1]Patent: US2003/176438,2003,A1

15
[ 84487-04-7 ]
[ 219766-89-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; acetic anhydride; In acetic acid;	PREPARATION EXAMPLE 4-4 To a suspension of 2-amino-6-bromo-3-nitropyridine (23.9 g) in acetic acid (48 ml) were added acetic anhydride (48 ml) and sulfuric acid (2.9 ml), and the mixture was heated at 65 C. for 40 min. The reaction mixture once became homogeneous and a product soon precipitated to give a suspension. The reaction mixture was allowed to cool and poured into cold water (480 ml), which was followed by stirring for 30 min. The precipitate was collected by filtration and washed with water to give a crude product. This was suspended in ether (60 ml) and collected by filtration to give 2-(acetamido)-6-bromo-3-nitropyridine as a pale-yellow powder (27.2 g). 1H-NMR (CDCl3): 2.54 (3H s), 7.33 (1H, d, J=8 Hz), 8.33 (1H, d, J=8 Hz), 9.95 (1H, br s). MASS (ESI): m/e 258,260 (M-H)-.

Reference： [1]Patent: US6573274,2003,B1

16
[ 84487-04-7 ]
[ 275384-14-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; propionic acid; In di-isopropyl ether; water;	PREPARATION EXAMPLE 11-1 A mixture of 2-amino-6-bromo-3-nitropyridine (4.5 g), propionic acid anhydride (12.2 ml), propionic acid (12.2 ml) and conc. sulfuric acid (101 mg) was stirred in an oil bath at 65 C. for 30 min, and left standing overnight. Water (122 ml) was added to the reaction mixture under ice-cooling, and stirred at the same temperature for 30 min. The precipitate was collected by filtration, washed with water, suspended in diisopropyl ether (20 ml) and stirred at room temperature for 30 min. The precipitate was stirred and washed with diisopropyl ether to give 6-bromo-3-nitro-2-(propionylamino)pyridine (5.59 g) as a pale-brown powder. 1H-NMR (CDCl3): 1.27 (3H, t, J=6 Hz), 2.78 (2H, q, J=6 Hz), 7.34 (1H, d, J=8 Hz), 8.32 (1H, d, J=8 Hz), 9.86 (1H, br, s). MASS (ESI): m/z 275 (M+1).

Reference： [1]Patent: US6573274,2003,B1

17
active charcoal [ No CAS ]
[ 7439-89-6 ]
[ 84487-04-7 ]
[ 129012-04-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol (220 ml)-water; water;	PREPARATION EXAMPLE 16-1 To a suspension of 2-amino-6-bromo-3-nitropyridine (21.8 g) in ethanol (220 ml)-water (22 ml) was added iron powder (39.0 g) at room temperature. Conc. hydrochloric acid (0.8 ml) was added and the mixture was gradually heated with stirring to start the reaction. The mixture was refluxed under heating for 2 hr, and an insoluble matter was removed by filtration while hot. The solvent was evaporated under reduced pressure, and water (200 ml) and active charcoal were added to the resulting solid, which was followed by heating. The insoluble matter was removed by filtration while hot, and water was evaporated under reduced pressure from the filtrate to give 2,3-diamino-6-bromopyridine (9.00 g) as a green brown powder. To the resulting solid from the above reaction were added ethanol (100 ml)-water (100 ml) and the mixture was heated for dissolution.

Reference： [1]Patent: US6573274,2003,B1

18
ammonium [ No CAS ]
[ 55304-80-8 ]
[ 84487-04-7 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water;	PREPARATION EXAMPLE 4-3 To a suspension of <strong>[55304-80-8]2,6-dibromo-3-nitropyridine</strong> (5.00 g) in ethanol (10 ml) was added a solution (6.8 M, 15 ml) of ammonium/ethanol at room temperature, and the mixture was stirred at room temperature for 19 hr in a sealed container. Water (25 ml) was added to the reaction mixture, and the precipitate was collected by filtration and washed with ethanol. This was suspended in ethanol (55 ml), heated, and allowed to cool. The precipitate was collected by filtration to give 2-amino-6-bromo-3-nitropyridine as a yellow powder (3.19 g). 1H-NMR (DMSO-d6): 6.89 (1H, d, J=8 Hz), 8.24 (1H, d, J=8 Hz), 8.25(2H, br s). MASS (ESI): m/e 216,218 (M-H)-.

Reference： [1]Patent: US6573274,2003,B1

19
[ 869542-43-8 ]
[ 84487-04-7 ]
[ 933998-81-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃;Schlenk tube;Product distribution / selectivity;	Obtained (80%) from <strong>[84487-04-7]6-bromo-3-nitropyridin-2-amine</strong> and 5-tributylstannanyl-2- triisopropylsilanyloxazole, following the procedure described in Preparation 10, step b. δ 1H-NMR (CDCI3): 1.17 (d, 18H), 1.43 (m, 3H), 7.11 (d, 1 H), 7.85 (s, 1 H), 8.48 (d,1 H).ESI/MS m/e: 363 ([M+H]+, C17H26N4O3Si)

Reference： [1]Patent: WO2007/39297,2007,A1 .Location in patent: Page/Page column 39

20
[ 7646-69-7 ]
[ 84487-04-7 ]
C₅H₃BrN₃O₂^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 20℃; for 1h;	A solution of <strong>[84487-04-7]6-bromo-3-nitro-pyridin-2-ylamine</strong> (750 mg, 3.44 mmol) in THF (20 mL) was treated with NaH (413 mg, 10.3 mmol) at room temperature for 1 h. Simultaneously a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (969 mg, 4.47 mmol, prepared as described in Example B) in DCM (20 mL) was treated with oxalyl chloride (390 μL, 4.47 mmol) and DMF (4 drops) at room temperature for 1 h. The acid chloride solution was concentrated to dryness in vacuo, taken up in THF (10 mL), and added to the sodium anilide solution. The resulting mixture was stirred at room temperature for 15 min, quenched with saturated aqueous NH4Cl (50 mL), and extracted twice with EtOAc (60 mL, 20 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: Flow rate=25 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 1 min, then 1:99 to 3:17 v/v over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 10.48 (br. s., 1H), 8.31 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 4.12 (s, 3H), 1.42 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C14H15BrClN5O3: 416.0 (M+H); Measured: 416.1.; A solution of <strong>[84487-04-7]6-bromo-3-nitro-pyridin-2-ylamine</strong> (500 mg, 2.29 mmol) in THF (10 mL) was treated with NaH (275 mg, 6.88 mmol) at room temperature for 1 h. Simultaneously a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (524 mg, 3.10 mmol, prepared as described in Example I) in DCM (10 mL) was treated with oxalyl chloride (270 μL, 3.10 mmol) and DMF (2 drops) at room temperature for 1 h. The acid chloride solution was concentrated to dryness in vacuo, taken up in THF (10 mL), and added to the sodium anilide solution. The resulting mixture was stirred at room temperature for 15 min, quenched with saturated aqueous NH4Cl (50 mL), and extracted twice with EtOAc (50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: Flow rate=25 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 1 min, then 1:99 to 3:17 v/v over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide as a solid. 1H-NMR (400 MHz, CDCl3) δ: 10.85 (br. s., 1H), 8.37 (d, J=8.6 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.03 (s, 1H), 1.39 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C13H13BrN4O4: 369.0 (M+H); Measured: 369.0.

Reference： [1]Patent: US2011/218197,2011,A1 .Location in patent: Page/Page column 66-67

21
[ 84487-04-7 ]
[ 98-80-6 ]
[ 102266-15-9 ]

Yield	Reaction Conditions	Operation in experiment
56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation;	To a solution of compound 1 (2.5 g, 14.5 mmol) in DME (8 nil), EtOH (4 nil), and H2O (4 ml) was added compound 2 (3.54 g, 29 mmol), Pd(PPh3)4 (335 mg, 0.29 mmol), and Na2CO3 (2.3 g, 21.7 mmol) under a nitrogen atmosphere. The reaction mixture was microwaved at 100 C. for 0.5 h, and extracted with EA (2×30 ml). The organic layers were combined and purified by gel chromatography (PE:EA=4:1) to afford the desired product of compound 3 (1.74 g, 56%)
0.280 g	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation;	To a stirred solution of <strong>[84487-04-7]6-bromo-3-nitropyridin-2-amine</strong> (CAS Number 84487-04-7; 0.500 g, 2.29 mmol) in DME-water-EtOH mixture (5:0.25:0.25; 5.5 ml) was added Na2CO3 (0.360 g, 3.44 mmol) and phenylboronic acid (0.550 g, 4.59 mmol) at rt. The reaction mixture was degassed withnitrogen gas for 15 mm and Pd(PPh3)4 (0.053g, 0.05 mmol) was added into the reaction mixture at the same temperature. The resulting reaction mixture was heated at 100C for 30 mm under microwave irradiation then cooled to rt. Two parallel reactions with 500 mg (each) of 6-bromo-3-nitropyridin-2- amine were carried out under similar reaction conditions and all three batches were combined prior to work-up. The combined mixtures were poured into water (50 ml) and were extracted with EtOAc (2 x50 ml). Combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (3% EtOAc in hexane) yielding 3-nitro-6-phenylpyridin-2-amine (0.280 g, 1.34 mmol). LCMS: Method C, 1.979 mi MS: ES+ 216.28.

Reference： [1]Patent: US2014/128391,2014,A1 .Location in patent: Paragraph 0217; 0218; 0219
[2]Patent: WO2018/60691,2018,A1 .Location in patent: Page/Page column 58; 59

22
[ 84487-04-7 ]
[ 411235-57-9 ]
[ 1552286-03-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5702 - 5713

23
[ 100-44-7 ]
[ 84487-04-7 ]
C₁₂H₁₀BrN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In acetonitrile; at 60℃; for 16h;	To a solution of 50 (560 mg, 2.57 mrnol) in CH3CN (15 mL) was added K2CQ3(887 mg, 6.43 mmoi) and benzyl chloride (484 mg, 2.83 mmoi). The reaction was heated at 60 "C for 16 h. The mixture was diluted with ethyl acetate (100 mL), filtered and concentrated to give 51 (790 mg, 100%) as a yellow solid: NM (300 MHz, CDCI3) δ 8.58 (br s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7,46-7.35 (m, 5H), 6.82 (d, J = 8.7 Hz, 1H), 4.82 (d, J = 5.7 Hz, 2H).

Reference： [1]Patent: WO2015/2754,2015,A2 .Location in patent: Paragraph 0248

24
[ 1319255-87-2 ]
[ 84487-04-7 ]
2-[5-(6-amino-5-nitropyridin-2-yl)pyrimidin-2-yl]propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Microwave irradiation;	EXAMPLE 2 (METHOD A)4-( 3-[(2,5-Dichlorophenyl)methyl1-5-(pyridin-4-yl)imidazo[4,5-b1pyridin-2-yH - methoxy)benzamideA microwave vial was charged with a solution of Example 1 (0.2 g, 0.3 mmol) in1,4-dioxane (3 mL) and water (1 mL). Pyridin-4-ylboronic acid (0.05 g, 0.42 mmol) and2M aqueous sodium carbonate solution (1 mL) were added, and the reaction mixture was degassed for 10 minutes. Pd(PPh3)4 (0.04 g, 0.10 mmol) was added and the reactionmixture was degassed for 10 minutes, then heated at 100C for 60 minutes in a Biotagemicrowave reactor. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through a Celite pad. The organic layer was separated, dried over anhydroussodium sulphate, and concentrated in vacuo. The residue was purified by preparativeHPLC, yielding the title compound (1 mg, 8%) as a white solidINTERMEDIATE 212-15 -(6-Amino-S -nitropyridin-2-yl)pyrimidin-2-yllpropan-2-olPrepared from 2- [5 -(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidin-2-yl] - propan-2-ol (4.19 g, 15.85 mmol), <strong>[84487-04-7]6-bromo-3-nitropyridin-2-amine</strong> (3.00 g, 13.21 mmol), cesium carbonate (6.45 mg, 19.82 mmol), 1,4-dioxane/water solution (9:1, 50 mL) and[1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (483.3 mg, S mol %) in accordance with Method A to give the title compound (3.03 g, 73%). H (400 MHz, CDC13) 9.31 (s, 2H), 8.57 (d,J8.6 Hz, 1H), 7.21 (d,J8.6 Hz, 1H), 4.60 (s, 1H), 1.89 (br s, 1H), 1.64 (s, 6H). LCMS (ESj 276.14 (M+H), RT 3.54 minutes.

Reference： [1]Patent: WO2015/86509,2015,A1 .Location in patent: Page/Page column 100; 109

25
[ 4891-38-7 ]
[ 84487-04-7 ]
methyl 5-bromo-8-nitro-3-phenylimidazo[1,2-a]pyridine-2-carboxylate [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 1094 - 1102

26
[ 84487-04-7 ]
3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ No CAS ]

Reference： [1]Patent: US6573274,2003,B1
[2]Patent: US6348474,2002,B1
[3]Patent: US6348474,2002,B1

27
[ 84487-04-7 ]
[ 219764-74-6 ]

Reference： [1]Patent: US6573274,2003,B1
[2]Patent: US6348474,2002,B1
[3]Patent: US6348474,2002,B1

28
[ 84487-04-7 ]
3-(4-(1-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ No CAS ]

Reference： [1]Patent: US6573274,2003,B1
[2]Patent: US6348474,2002,B1
[3]Patent: US6348474,2002,B1

29
[ 84487-04-7 ]
methyl 3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate [ No CAS ]

Reference： [1]Patent: US6573274,2003,B1
[2]Patent: US6348474,2002,B1
[3]Patent: US6348474,2002,B1

30
[ 84487-04-7 ]
[ 219763-98-1 ]

Reference： [1]Patent: US6573274,2003,B1
[2]Patent: US6348474,2002,B1
[3]Patent: US6348474,2002,B1

31
[ 84487-04-7 ]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine [ No CAS ]