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[ CAS No. 152684-30-5 ]

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CAS No. :152684-30-5 MDL No. :MFCD07374968
Formula : C6H5BrN2O3 Boiling Point : 303.9°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :233.02 g/mol Pubchem ID :15645664
Synonyms :

Safety of [ 152684-30-5 ]

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 [ 152684-30-5 ]

  • Upstream synthesis route of [ 152684-30-5 ]
  • Downstream synthetic route of [ 152684-30-5 ]

[ 152684-30-5 ] Synthesis Path-Upstream   1~11

  • 1
  • [ 67-56-1 ]
  • [ 67443-38-3 ]
  • [ 152684-30-5 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: at 20℃; Cooling
Stage #2: at 0 - 20℃; for 17 h;
To a cooled solvent of MeOH (50.0 mL) was added Na (2.90 g, 126.4 mmol) portion-wise, then the mixture was warmed to rt and stirred until Na was all dissolved, then the solution was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (10.0 g, 42.12 mmol, Shanghai long sheng hua gong, china) in MeOH (100 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, then warmed up to rt and stirred further for 16 hours, then concentrated to 80 mL and quenched with water (100 mL). The precipitate was filtered, washed with water (50 mL*2) and dried under infrared light to give the title compound as a pale yellow solid (9.62 g, 98percent). MS (ESI, pos. ion) m/z: 233.0 [M+H]+.
82% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol)was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) inmethanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h. Themixture was concentrated under reduced pressure, and the residue was diluted with water (200mL). The resulting precipitate was collected by filtration, washed with water, and dried underreduced pressure to give the title compound (12.0 g, 82percent yield) as a brown solid.
71.4% at 0 - 20℃; for 19 h; To a solution of sodium methanolate (0.52 g, 9.64 mmol) in MeOH (10 mL) wasadded 5-bromo-2-chloro-3-nitropyridine (0.57 g, 2.41 mmol) at 0°C. The reaction was stirred at0°C for 1 h, then warmed up to rt and stired further for 18 h. The reaction was quenched withH20 (20 mL), adjusted to pH 7 with 3M HCl and then filtered. The seperated organic phase wasconcentrated in vacuo to give the title compound as a light yellow solid (0.4 g, 71.4percent). Thetitle compound was characterized by LC-MS and 1H NMR as shown below:LC-MS (ESI, pos. ion) m/z: 233 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 3.93 (s, 3H), 8.08 (s, 1H), 8.89 (s, 1H).
Reference: [1] Patent: US2014/134133, 2014, A1, . Location in patent: Paragraph 0384
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3534 - 3541
[3] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 7, p. 737 - 741
[4] Patent: WO2014/22128, 2014, A1, . Location in patent: Paragraph 0149
  • 2
  • [ 15862-34-7 ]
  • [ 74-88-4 ]
  • [ 152684-30-5 ]
YieldReaction ConditionsOperation in experiment
45% With silver carbonate In chloroform at 20℃; for 48 h; Example 4N-(2-Methyl-3-(5-(5-(4-methylpiperazin-l-yl)pyridine-2-ylamino)-6-oxo-l,6- dihydropyridin-3-yl)phenyl)-4,5,6,7-tetrahydrobenzo[Z>]thiophene-2- carboxamide (19); 5-Bromo-2-methoxy-3-nitropyridine (15)[00197] In a 1 L, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-3-nitropyridin-2-ol (50.0 g, 0.23 mol) in CHCl3 (500 mL) under nitrogen in the dark (wrapped in aluminum foil.) To this solution was added Ag2CO3 (75.5 g, 0.28 mol) and MeI (142.0 mL, 2.3 mol). After the mixture was stirred for 48 h at room temperature, it was filtered through a pad of Celite, washed with CH2Cl2, and concentrated. The crude mixture was purified by column chromatography (EtOAc:Hexane, 1:4) to give 24.0 g (45percent) of 5-bromo-2- methoxy-3-nitropyridine (15) as a solid.
34% With silver carbonate In methylene chloride at 20℃; for 48 h; Inert atmosphere; Darkness Method B: to a suspension of 14 (5.0 g, 22.8 mmol) in anhydrous CH3Cl (50 mL) under N2 in the dark (wrapped in aluminum foil) was added Ag2CO3 (7.55 g, 28.0 mmol), followed by CH3I (14.2 mL, 230.0 mmol). After stirring at rt for 48 h, the reaction mixture was filtered through a pad of Celite, washed with abundant CH2Cl2, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10:1 hexanes/EtOAc) to afford 16 (1.86 g, 34percent) as a pale yellow solid. The analytical data were same as aforementioned.
Reference: [1] Patent: WO2008/33854, 2008, A1, . Location in patent: Page/Page column 74
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
  • 3
  • [ 67-56-1 ]
  • [ 67443-38-3 ]
  • [ 124-41-4 ]
  • [ 152684-30-5 ]
YieldReaction ConditionsOperation in experiment
98% at 0 - 20℃; for 19.1667 h; 5 -Bromo-2-chloro-3 -nitropyridineTo a stirred solution of 5 -bromo-2-chloro-3 -nitropyridine (20.4 g, 86 mMol) in methanol (75 rnL) at 0 0C in an ice bath was added dropwise a solution of 25 wtpercent sodium methoxide in methanol (20 mL, 87 mMol) and methanol (20 mL) over 10 minutes. After stirring at 0 0C for 1 h the reaction was allowed to warm to RT and stirred for 18 h. The reaction was concentrated under vacuum to aproximately half its volume then poured into ice water (-500 mL). The precipitate that formed was filtered off , washed with cold water, and dried under vacuum to give the title product (19.7 g, 98percent) as a pale yellow solid: MS(ES)+ m/e 233.2 [M+H]+.
71.4% at 0 - 20℃; for 19 h; To a solution of sodium methanolate (0.52 g, 9.64 mmol) in MeOH (10 mL) was added 5-bromo-2-chloro-3-nitropyridine (0.57 g, 2.41 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, then warmed to rt and stirred for 18 hours. The mixture was quenched with water (20 mL), adjusted to pH=7 with aq. HCl (3 M), and then filtered. The organic phase was separated and concentrated in vacuo to give the title compound as a light yellow solid (0.4 g, 71.4percent).
Reference: [1] Patent: WO2008/157191, 2008, A2, . Location in patent: Page/Page column 78
[2] Patent: US2014/234254, 2014, A1, . Location in patent: Paragraph 0297; 0298; 0299
  • 4
  • [ 67443-38-3 ]
  • [ 124-41-4 ]
  • [ 152684-30-5 ]
YieldReaction ConditionsOperation in experiment
98% at 0 - 20℃; for 19 h; a) 5 -bromo-2-(methyloxy)-3 -nitropyridine. To a stirred solution of 5-bromo-2-chloro-3-nitropyridine (86 mmol) in methanol (75 mL) at 0 0C was added drop wise a solution of 25percent w/w sodium methoxide in methanol (20 mL, 87 mmol) and methanol (20 mL) over 10 min. After stirring at 0 0C for 1 h the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was concentrated under vacuum to approximately half its volume then poured into ice water (-500 mL). The precipitate that formed was filtered, washed with cold water, and dried under vacuum to give the title product (98percent) as a pale yellow solid. MS(ES)+ m/e 233.2 [M+H]+.
98% at 0 - 20℃; for 19.1667 h; To a stirred solution of 5-bromo-2-chloro-3-nitropyridine (86 mmol) in methanol (75 mL) at 0 0C was added dropwise a solution of 25 wtpercent sodium methoxide in methanol (87 mmol) and methanol (20 mL) over 10 min. After stirring at 0 0C for 1 h the reaction was allowed to warm to room temperature and was stirred for 18 h. The reaction was concentrated under vacuum to aproximately half its volume then poured into ice water (-500 mL). The precipitate that formed was filtered, washed with cold water, and dried under vacuum to give the title product (98percent) as a pale yellow solid. MS(ES)+ m/e 233.2 [M+H]+.
95% at 0 - 20℃; for 24 h; Reflux A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for lh. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).
95% at 0 - 20℃; Reflux A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for lh. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).
95% at 0 - 20℃; Reflux A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitropyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for 1h. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).
95% at 0 - 20℃; Reflux A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0° C. and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise.
The mixture is stirred at RT over night and then stirred under reflux for 24 h.
The precipitate is filtered off, suspended in water and the suspension is stirred for 1 h.
The product is filtered off and dried and vacuum at 60° C. Yield: 18.7 g (95percent).
90% at 0 - 20℃; for 16.16 h; Intermediate 1; λ/-[5-Bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide; a) 5-bromo-2-(methyloxy)-3-nitropyridine; To a cooled (0 0C) solution of S-bromo-l-chloro-S-nitropyridine (50 g, 211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20percent sodium methoxide (50 mL, 211 mmol) solution. The reaction, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h.The reaction was filtered and the precipitate diluted with water (200 mL) and stirred for 1 h. The solids were filtered, washed with water (3 x 100 mL) and dried in a vac oven (40 0C) to give 5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4percent yield) as a pale yellow powder. The original filtrate was concentrated in vacuo and diluted with water (150 mL). Saturated ammonium chloride (25 mL) was added and the mixture stirred for 1 h. The solids were filtered, washed with water, and <n="87"/>dried in a vac oven (40 0C) to give a second crop of 5-bromo-2-(methyloxy)-3- nitropyridine (9 g, 38.6 mmol, 18.34 percent yield). Total yield = 90percent. MS(ES)+ m/e 232.8, 234.7 [M+H]+.
90% at 0 - 20℃; for 16 h; a)
5-bromo-2-(methyloxy)-3-nitropyridine
To a cooled (0° C.) solution of 5-bromo-2-chloro-3-nitropyridine (50 g, 211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20percent sodium methoxide (50 mL, 211 mmol) solution.
The reaction, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h.
The reaction was filtered and the precipitate diluted with water (200 mL) and stirred for 1 h.
The solids were filtered, washed with water (3*100 mL) and dried in a vac oven (40° C.) to give 5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4percent yield) as a pale yellow powder.
The original filtrate was concentrated in vacuo and diluted with water (150 mL).Saturated ammonium chloride (25 mL) was added and the mixture stirred for 1 h. The solids were filtered, washed with water, and dried in a vac oven (40° C.) to give a second crop of 5-bromo-2-(methyloxy)-3-nitropyridine (9 g, 38.6 mmol, 18.34percent yield). Total yield=90percent. MS(ES)+m/e 232.8, 234.7 [M+H]+.
83% at 0 - 50℃; for 12 h; 4.1.1
5-Bromo-2-methoxy-3-nitropyridine (2)
To a solution of 5-bromo-2-chloro-3-nitropyridine (1) (10.0 g, 42.37 mmol) in anhydrous methanol (40 mL) was added sodium methoxide solution (20 mL, 63.56 mmol) slowly at 0 °C.
The reaction mixture was then heated to 50 °C and stirred for 12 h.
After the completion of reaction, the mixture was filtered and the precipitate was washed with water.
The obtained solids were then dried under reduced pressure to give the title compound (8.12 g, 35.0 mmol, 83percent yield) with light yellow. ESI-MS: m/z = 233 [M+H]+.
81.5% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro- 3-nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reactionmixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 8 1.5percent yield) as a brown solid. 44 NMR (400MHz, CDCI3): 6 8.43 (d, Jr 2.4 Hz, 1 H), 8.38 (d,J 2.0 Hz, 1 H), 4.09 (s, 311).
81.5% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3- nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h, at which time TLC indicated the reaction had gone to completion. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12,0 g, 81.5percent yield) as a brown solid. H NMR (400MHz, CDC13): δ 8.43 (d, J= 2.4 Hz, 1 H), 8.38 (d, J = 2.0 Hz, 1 H), 4.09 (s, 3 H)
81.5% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3- nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 81.5percent yield) as a brown solid. 1H NMR (400MHz, CDC13): δ 8.43 (d, J= 2.4 Hz, 1 H), 8.38 (d, J= 2.0 Hz, 1 H), 4.09 (s, 3 H).
81.5% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) in MeOH (125 mL). The reaction was heated at refluxtemperature for 2 h and then concentrated under reduced pressure. The residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 8 1.5percent yield) as a brown solid.‘H NMR (400MHz, CDC13): 6 8.43 (d, J= 2.4 Hz, 1 H), 8.38 (d, J= 2.0 Hz, 1 H), 4.09 (s, 3 H).
71.4% at 0 - 20℃; for 19 h; At 0 , sodium methoxide (0.52g, 9.64mmol) in MeOH (10mL) was added 5-bromo-2-chloro-3-nitropyridine (0.57g, 2.41mmol).The reaction was maintained with stirring at 0 1 hour and then cooled to room temperature, stirring was continued for 18 hours.The reaction solution was added water (20 mL) after being quenched with 3M hydrochloric acid and adjusted to pH 7, and filtered.The separated organic phase was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.4g, 71.4percent)
62% at 0 - 20℃; Method A: to a cooled suspension of 15 (15.0 g, 63.2 mmol) in anhydrous MeOH (60 mL) was added 20percent NaOMe in MeOH (15 mL, 66.4 mmol) dropwise at 0 °C. After the reaction mixture was allowed to warm to rt and stirred overnight, the pale yellow precipitate was filtered off to give the crude product. The crude product was diluted with water and stirred for 1 h. The solid was collected by filtration, washed with water and dried to afford 16 (9.22 g, 62percent) as a pale yellow solid. The original filtrate was concentrated in vacuo and diluted with water. Saturated aqueous NH4Cl was added and the mixture was stirred for 1 h. The solid was collected by filtration, washed with water and dried in a vacuum oven (40 °C) to give the second crop of 16 (4.74 g, 32percent) as a pale yellow solid, mp 88-90 °C. 1H NMR (CDCl3) δ 8.45 (d, J = 2.5 Hz, 1H, Ar-H), 8.39 (d, J = 2.0 Hz, 1H, Ar-H), 4.11 (s, 3H, OCH3).
1.37 kg at 0 - 10℃; for 2.75 h; Inert atmosphere; Large scale 5-Bromo-2-(methyloxy)-3-nitropyridine
Method A
A solution of 25percent wt sodium methoxide in methanol (2.1 L) was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (1.70 kg) in methanol (6.6 L), stirred under nitrogen at 0-5° C.
The reaction mixture was stirred at 5-10° C. for 2.75 hours and then water (8.5 L) was added.
The reaction mixture was cooled to 20-25° C.
The mixture was then concentrated under vacuum and the resultant suspension was filtered, washed with water (8.5 L then 2*4.25 L) and the solid dried under vacuum to give the title compound as an off-white solid (1.37 kg).
1H NMR (400 MHz, Chloroform-d) δ (ppm) 8.46 (s, 1H), 8.40 (s, 1H).

Reference: [1] Patent: WO2009/39140, 2009, A1, . Location in patent: Page/Page column 52
[2] Patent: WO2008/150827, 2008, A1, . Location in patent: Page/Page column 80
[3] Patent: WO2012/101184, 2012, A1, . Location in patent: Page/Page column 56
[4] Patent: WO2012/101186, 2012, A1, . Location in patent: Page/Page column 53
[5] Patent: EP2546249, 2013, A1, . Location in patent: Paragraph 0210; 0211
[6] Patent: US2013/23533, 2013, A1, . Location in patent: Paragraph 0234; 0235
[7] Patent: WO2009/55418, 2009, A1, . Location in patent: Page/Page column 85-86
[8] Patent: US2013/317037, 2013, A1, . Location in patent: Paragraph 0106
[9] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[10] Patent: WO2016/77378, 2016, A1, . Location in patent: Page/Page column 88; 89
[11] Patent: WO2016/77380, 2016, A1, . Location in patent: Page/Page column 68; 69
[12] Patent: WO2016/77375, 2016, A1, . Location in patent: Page/Page column 85
[13] Patent: WO2016/123391, 2016, A1, . Location in patent: Page/Page column 164
[14] Patent: CN103539777, 2016, B, . Location in patent: Paragraph 0300; 0301
[15] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
[16] Patent: WO2010/139731, 2010, A1, . Location in patent: Page/Page column 170
[17] Patent: WO2012/32067, 2012, A1, . Location in patent: Page/Page column 57
[18] Patent: US2014/38991, 2014, A1, . Location in patent: Paragraph 0204; 0205; 0206
[19] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 5, p. 957 - 966
[20] Patent: US9326987, 2016, B2, . Location in patent: Page/Page column 163
  • 5
  • [ 13472-85-0 ]
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Reference: [1] Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812
  • 6
  • [ 15862-34-7 ]
  • [ 152684-30-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
  • 7
  • [ 152684-30-5 ]
  • [ 893440-50-1 ]
Reference: [1] Patent: WO2012/32067, 2012, A1,
[2] Patent: WO2012/174312, 2012, A2,
[3] Patent: US2013/190307, 2013, A1,
[4] Patent: US9326987, 2016, B2,
[5] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 3, p. 256 - 261
[6] Patent: WO2012/34526, 2012, A1,
  • 8
  • [ 152684-30-5 ]
  • [ 884495-39-0 ]
YieldReaction ConditionsOperation in experiment
97% With iron; ammonium chloride In ethanol; water for 15 h; Reflux To a suspension of 5-bromo-2-methoxy-3-nitropyridine (9.62 g, 41.3 mmol) in ethanol (100 mL) and water (10 mL) was added Iron powder (9.25 g, 165.2 mmol, Tianjin guangfukeji) and NH4Cl (8.83 g, 165.2 mmol). The mixture was heated to reflux and stirred further for 15 hours, then cooled to rt, and concentrated in vacuo. The residue was dissolved in 250 mL of EtOAc and the resulted solution was washed with saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL*2) and brine (150 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound as a yellow solid (8.16 g, 97percent). MS (ESI, pos. ion) m/z: 202.8 [M+H]+.
95% With water; iron; ammonium chloride In ethanol at 95℃; for 1 h; 5- Bromo-2-methoxypyridin-3-amine (16); [00198] In a 500 mL, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-2-methoxy-3-nitropyridine (15) (20.0 g, 0.086 mol), Fe (20.0 g, 0.36 mol), and NH4Cl (20.0 g, 0.36 mol) in EtOH/H2O (150 mL, 1:1). After heating at 95 0C for 1 h, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give 16.5 g (95 percent) of 5- bromo-2- <n="76"/>methoxypyridin-3-amine (16) as a solid.
86% With iron; ammonium chloride In ethanol; water for 1 h; Reflux To a suspension of 5-bromo-2-methoxy-3-nitropyridine (0.4 g, 1.72 mmol) in EtOH(5 mL) and H20 (5 mL) was added iron powder (0.38 g, 6.87 mmol) and NH4Cl (0.39 g, 7.21mmol). The reaction refluxed for 1 h, then cooled down to rt and concentrated in vacuo. Theresidue was diluted with EtOAc (1 0 mL) and the resulted mixture was filtered through a pad ofcelite. The filtrate was extracted with EtOAc (10 mL x 3) and the combined organic phases werewashed with brine (10 mL), dried over anhydrous Na2S04 and concentrated in vacuo to give thetitle compound as a yellow solid (0.3 g, 86percent). The title compound was characterized byLC-MS and 1H NMR as shown below:LC-MS (ESI, pos. ion) m/z: 203 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 3.92 (s, 3H), 4.86 (s, 2H), 7.03 (d, J = 2.0 Hz, 1H), 7.41 (d,J = 2.0 Hz, 1H).
86% With ethanol; iron; ammonium chloride In water for 1 h; Reflux To a suspension of 5-bromo-2-methoxy-3-nitropyridine (0.4 g, 1.72 mmol) in EtOH (5 mL) and H2O (5 mL) were added iron powder (0.38 g, 6.87 mmol) and NH4Cl (0.39 g, 7.21 mmol). The reaction was heated to reflux and stirred further for 1 hour, and then concentrated in vacuo. The residue was diluted with EtOAc (10 mL) and the resulted mixture was filtered through a pad of CELITE®. The filtrate was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (0.30 g, 86percent). [0301] MS (ESI, pos. ion) m/z: 203.0 [M+H]+; [0302] 1H NMR (400 MHz, CDCl3) δ (ppm): 3.92 (s, 3H), 4.86 (s, 2H), 7.03 (d, J=2.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H).
86% With iron; ammonium chloride In ethanol; water for 1 h; Reflux The 5-bromo-2-methoxy-3-nitro pyridine (0.4g, 1 . 72mmol) suspended in EtOH (5 ml) and H 2 O (5 ml) in the mixed solution, adding Fe powder (0.38g, 6 . 87mmol) and NH 4 Cl (0.39g, 7 . 21mmol). Reaction liquid heating reflux for 1 hour, cooling to room temperature, and concentrating under reduced pressure. For residual EtOAc (10 ml) dilution, diatomite filter for the resulting mixture. Filtrate using EtOAc (10mLx3) extraction, the organic phase of the first combined and salt water (10 ml) to wash, anhydrous Na 2 SO 4 drying, and concentrating under reduced pressure, to obtain the title compound as yellow solid (0.3g, 86
81%
Stage #1: With tin(ll) chloride In ethyl acetate for 3 h; Heating / reflux
Stage #2: With sodium hydroxide In dichloromethane; water; ethyl acetate at 0℃; for 2 h;
b) 5 -bromo-2-(methyloxy)-3 -pyridinamine. To a solution of 5 -bromo-2-(methyloxy)-3 -nitropyridine (82 mmol) in ethyl acetate (300 mL) was added tin(II)chloride dihydrate (328 mmol). The reaction mixture was stirred for 3 h at reflux. (Caution: during the initial exotherm, that subsided after ~10 min, the heating bath was temporarily removed.) After cooling to room temperature, the mixture was concentrated under vacuum to a pale yellow slurry. The slurry was poured into 6 N aq. sodium hyroxide (300 mL), ice water (300 mL), and dichloromethane (300 niL) and stirred for 2 h until mostly dissolved. The small amount of insoluble material was filtered off and the organic phase was separated, dried over sodium sulfate, filtered, and evaporated to dryness. The resultant brown oil was triturated with hexanes to obtain a solid, which was filtered and dried in vacuo to afford the title product (81percent) as a pale green solid. MS(ES)+ m/e 202.8 [M+H]+.
81%
Stage #1: With tin(ll) chloride In ethyl acetate for 3 h; Heating / reflux
Stage #2: With sodium hydroxide; water In dichloromethane at 0℃; for 2 h;
3 - Amino-5 -bromo-2-methoxypyridineTo 5 -Bromo-2-methoxy-3 -nitropyridine (19.0 g, 82 mmol) in EtOAc (300 mL) was added Tin(II)chloride dihydrate (74 g, 328 mmol). The reaction was stirred and refluxed for 3 h. (During the initial exotherm, that subsided after ~10 minutes, the heating bath was temporarily removed.) After cooling to RT the reaction was concentrated under vacuum to a pale yellow slurry. The slurry was poured into aq. 6 N NaOH (300 mL), ice (300 mL) and CH2CI2 (300 mL) and stirred for 2 h till mostly dissolved. The small amount of insoluble material was filtered off, the organic phase separated, dried (Na2SO4), filtered and evaporated to dryness. Trituration with hexanes solidified the brown oil which remained. Filtration and drying under vacuum gave the title product (13.40 g, 81percent) as a pale green solid: MS(ES)+ m/e 202.8 [M+H]+.
77% With tin(II) chloride dihdyrate In acetic anhydride for 3 h; Reflux Step D 5-bromo-2-methoxypyridin-3-amine[00298] Tin (II) chloride dihydrate (87 g, 386.2 mmol) was added into a solution of 5- bromo-2-methoxy-3-nitropyridine (18 g, 72.2 mmol) in acetyl acetae (450 mL) at r.t. and the resulting mixture was refluxed for 3 hours with TLC monitoring. After the full conversion of starting material, the reaction mixture was cooled to r.t. and slowly poured into 6 N NaOH (500 mL) and stirred for a period of 10 minutes. The precipitate was filtered out with suction, and the filtrate was extracted with EtOAc (500 mL x 3). The combined organic layer was dried over Na2S04, filtered, and concentrated to dry to give a residue which was purified with column chromatography (EtOAc: petroleum ether = 1 : 4 as eluent) to give the product as a white solid (12 g, 77percent). LC/MS, ESI, m/z, 203, 205 (m+1 )+, Br pattern found.
76% With tin(II) chloride dihdyrate In ethyl acetate for 4 h; Reflux To a solution of 16 (12.0 g, 51.7 mmol) in EtOAc (200 mL) was added SnCl2*2H2O (50.0 g, 221.6 mmol). The reaction mixture was stirred and heated at reflux for 4 h. After removal of the solvent, the residue was treated with 2 N aqueous NaOH and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (9:1 hexanes/EtOAc) to afford 17 (8.0 g, 76percent) as a pale yellow solid, mp 58-60 CH3. 1H NMR (CDCl3) δ 7.58 (d, J = 2.0 Hz, 1H, Ar-H), 6.98 (d, J = 2.0 Hz, 1H, Ar-H), 3.96 (s, 3H, OCH3).
76% With tin(II) chloride dihdyrate In ethyl acetate at 50℃; for 3 h; Inert atmosphere 4.1.2
5-Bromo-2-methoxypyridin-3-amine (3)
A mixture of 5-bromo-2-methoxy-3-nitropyridine (2) (5.0 g, 21.55 mmol) and tin(II) chloride dihydrate (24.35 g, 107.75 mmol) was dissolved into ethyl acetate (0.2 L) and stirred at 50 °C for 3 h under a nitrogen atmosphere.
The mixture was dissolved in EtOAc (0.8 L), washed with 1 N sodium hydroxide (1.2 L) twice, water twice, dried over magnesium sulfate and concentrated to give the title compound (3.31 g, 16.39 mmol, 76percent yield) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ 7.37 (d, J = 2.0 Hz, 1H, Ar-H), 6.97 (d, J = 2.0 Hz, 1H, Ar-H), 5.28 (s, 2H, NH2), 3.82 (s, 3H, OCH3). ESI-MS: m/z = 203 [M+H]+.
75% With stannous chloride dihydrate In ethyl acetate for 3 h; Reflux A solution of 985 mg (4.23 mmol) C-4 in 10 mL EtOAc is treated with 3.82 g (16.9 mmol) tin-II-chloride dihydrate. The mixture is stirred under reflux for 3 h. After cooling to RT, the solvent is removed under reduced pressure and the crude product is taken up in 9.5 mL aqueous 2 N NaOH. After stirring at RT for 1 h, DCM is added and the mixture is filtered over Celite. The aqueous phase is extracted with DCM, the combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 647 mg (75percent).
58.7%
Stage #1: With tin(ll) chloride In ethyl acetate for 6 h; Heating / reflux
Stage #2: With sodium hydroxide In water at 20℃; for 1 h;
b) 5-bromo-2-(methyloxy)-3-pyridinamine; To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin(II) chloride dihydrate (174 g, 772 mmol). The reaction mixture was heated at reflux for 4 h. LC/MS indicated some starting material remained, so added 20 molpercent tin (II) chloride dihydrate and continued to heat at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with 2 N sodium hydroxide and the mixture stirred for 1 h. The mixture was then with methylene chloride (1 L), filtered through Celite, and washed with methylene chloride (500 mL). The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7 percent yield). The product was used crude in subsequent reactions. MS(ES)+ m/e 201.9, 203.9 [M+H]+.
58.7%
Stage #1: With tin(II) chloride dihdyrate In ethyl acetate for 6 h; Reflux
Stage #2: at 20℃; for 1 h;
b)
5-bromo-2-(methyloxy)-3-pyridinamine
To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin(II) chloride dihydrate (174 g, 772 mmol).
The reaction mixture was heated at reflux for 4 h.
LC/MS indicated some starting material remained, so added 20 mol percent tin (II) chloride dihydrate and continued to heat at reflux.
After 2 h, the reaction was allowed to cool to ambient temperature and concentrated in vacuo.
The residue was treated with 2 N sodium hydroxide and the mixture stirred for 1 h.
The mixture was then with methylene chloride (1 L), filtered through Celite, and washed with methylene chloride (500 mL).
The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7percent yield).
The product was used crude in subsequent reactions. MS(ES)+ m/e 201.9, 203.9 [M+H]+.
1.13 kg at 20 - 25℃; Large scale 5-Bromo-2-(methyloxy)-3-pyridinamine
Iron powder (1.17 kg) was added to a suspension of 5-bromo-2-(methyloxy)-3-nitropyridine (1.36 kg) in IMS (6.1 L), stirred under nitrogen at 20-25° C. Water (0.8 L) was then added and the mixture cooled to less than 10° C.
Aqueous hydrochloric acid (0.8 L concentrated hydrochloric acid and 0.8 L water) was then added to the reaction mixture, maintaining the temperature below 10-15° C.
The suspension was warmed to 20-25° C. and then stirred at this temperature for 23 hours.
The suspension was filtered, the filter cake washed with IMS (2*2.7 L) and the combined filtrates concentrated under vacuum.
Water (4.1 L) was added slowly to the concentrated solution and the resulting suspension was held at 20-25° C. for 1.75 hours.
The resultant suspension was filtered, washed with water (2*6.8 L) and the solid dried under vacuum to give the title compound as an off-white solid (1.13 kg). LCMS (Method B): Rt 2.16 mi MH 204.

Reference: [1] Patent: US2014/134133, 2014, A1, . Location in patent: Paragraph 0387
[2] Patent: WO2008/33854, 2008, A1, . Location in patent: Page/Page column 74-75
[3] Patent: WO2014/22128, 2014, A1, . Location in patent: Paragraph 0150
[4] Patent: US2014/234254, 2014, A1, . Location in patent: Paragraph 0300; 0301; 0302
[5] Patent: CN103539777, 2016, B, . Location in patent: Paragraph 0304; 0305
[6] Patent: WO2009/39140, 2009, A1, . Location in patent: Page/Page column 52-53
[7] Patent: WO2008/157191, 2008, A2, . Location in patent: Page/Page column 78
[8] Patent: WO2012/174312, 2012, A2, . Location in patent: Page/Page column 214
[9] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
[10] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[11] Patent: EP2546249, 2013, A1, . Location in patent: Paragraph 0212; 0213
[12] Patent: WO2009/55418, 2009, A1, . Location in patent: Page/Page column 86
[13] Patent: US2013/317037, 2013, A1, . Location in patent: Paragraph 0107
[14] Patent: WO2012/32067, 2012, A1, . Location in patent: Page/Page column 57-58
[15] Patent: WO2012/101184, 2012, A1, . Location in patent: Page/Page column 56
[16] Patent: WO2012/101186, 2012, A1, . Location in patent: Page/Page column 54
[17] Patent: US2013/23533, 2013, A1, . Location in patent: Paragraph 0236; 0237
[18] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 243 - 251
[19] Patent: US2014/38991, 2014, A1, . Location in patent: Paragraph 0208; 0209; 0210
[20] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 5, p. 957 - 966
[21] Patent: US9326987, 2016, B2, . Location in patent: Page/Page column 163; 164
[22] Patent: WO2008/150827, 2008, A1,
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YieldReaction ConditionsOperation in experiment
81% With potassium acetate In 1,4-dioxane for 2 h; Reflux The mixture of 5-bromo-2-methoxy-3-nitropyridine (5 g, 21 .5 mmol),4,4,4',4',5,5,5',5' -octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (6.6 g, 25.8 mmol) ,PdCl2(dppf)-CH2Cl2 (500 mg) and potassium acetate (6.3 g, 64.5 mmol) in anhydrous 1 ,4-dioxane (200 ml_) was refluxed for 2h. Then the solvents were removed. The crude product was purified by chromatography on silica gel using petroleumether:EtOAc =10:1 as eluent to afford 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine in 81 percent yield (5 g). m/z 281 (M+H)+.
81% With palladium dichloro <1,1'-bis(diphenylphosphino)ferrocene>; potassium acetate In 1,4-dioxane for 2 h; Reflux The mixture of 5-bromo-2-methoxy-3-nitropyridine (5 g, 21.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.6 g, 25.8 mmol), PdCl2(dppf)-CH2Cl2 (500 mg) and potassium acetate (6.3 g, 64.5 mmol) in anhydrous 1,4-dioxane (200 mL) was refluxed for 2 h. Then the solvents were removed. The crude product was purified by chromatography on silica gel using petroleum ether:EtOAc=10:1 as eluent to afford 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in 81percent yield (5 g). m/z 281 (M+H)+.
80% With potassium acetate In N,N-dimethyl-formamide at 80℃; AL 2-Methoxy-3-nitro-5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridine; To a dry flask was added 5-bromo-2-methoxy-3-nitropyridine (1.3 g, 5.0 mmol),4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.6 g, 6.4 mmol), and Pd(dppf)Cl2 (0.2 g, 0.25 mmol). Potassium acetate (1.5 g, 15 mmol) was weighed directly into the flask. The flask was then evacuated and back filled with N2. Anhydrous N,N-dimethylformamide (30 mL) was added and the reaction was heated at 80 0C in an oil bath overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting material was purified by silica gel chromatography (eluting with 0-50percent ethyl acetate in hexane) to yield the product (0.2 g, 15percent). ESI-MS m/z calc. 280.12, found 199.1 (MW[-C6Hio]+l)+. Retention time 0.7 minutes.
Reference: [1] Patent: WO2012/34526, 2012, A1, . Location in patent: Page/Page column 33
[2] Patent: US2013/190307, 2013, A1, . Location in patent: Paragraph 0158; 0159
[3] Patent: WO2008/141119, 2008, A2, . Location in patent: Page/Page column 105
[4] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 3, p. 256 - 261
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Reference: [1] Patent: WO2012/32067, 2012, A1,
[2] Patent: WO2012/32067, 2012, A1,
[3] Patent: WO2012/32067, 2012, A1,
[4] Patent: US2014/134133, 2014, A1,
[5] Patent: US9326987, 2016, B2,
[6] Patent: US9326987, 2016, B2,
  • 11
  • [ 152684-30-5 ]
  • [ 1086062-66-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
[2] Patent: US2013/317037, 2013, A1,
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