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[ CAS No. 4487-59-6 ] {[proInfo.proName]}

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Chemical Structure| 4487-59-6
Chemical Structure| 4487-59-6
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Product Details of [ 4487-59-6 ]

CAS No. :4487-59-6 MDL No. :MFCD00006222
Formula : C5H3BrN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :HUUFTVUBFFESEN-UHFFFAOYSA-N
M.W :202.99 Pubchem ID :78240
Synonyms :

Calculated chemistry of [ 4487-59-6 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 40.76
TPSA : 58.71 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.27
Log Po/w (XLOGP3) : 2.02
Log Po/w (WLOGP) : 1.75
Log Po/w (MLOGP) : 0.04
Log Po/w (SILICOS-IT) : -0.05
Consensus Log Po/w : 1.01

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.75
Solubility : 0.362 mg/ml ; 0.00178 mol/l
Class : Soluble
Log S (Ali) : -2.88
Solubility : 0.267 mg/ml ; 0.00132 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.26
Solubility : 1.11 mg/ml ; 0.00546 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 3.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.16

Safety of [ 4487-59-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330 UN#:N/A
Hazard Statements:H302-H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4487-59-6 ]

* 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 [ 4487-59-6 ]
  • Downstream synthetic route of [ 4487-59-6 ]

[ 4487-59-6 ] Synthesis Path-Upstream   1~37

  • 1
  • [ 4487-59-6 ]
  • [ 13534-97-9 ]
YieldReaction ConditionsOperation in experiment
91.3% With hydrogenchloride; iron In ethanol; water for 5 h; Reflux To a solution of 2-bromo-5-nitropyridine (2.03 g, 10 mmol) in ethanol (48 mL), iron powder (2.8 g, 50 mmol), concentrated hydrochloric acid (1.9 mL) and water (9.1 mL) were sequentially added.
The mixture was reacted under reflux for 5 h, cooled and filtrated.
The filtrate was concentrated, adjusted to a pH of about 7 to 8 and extracted with DCM.
The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a reddish brown solid (1.58 g, 91.3percent yield).
74.4% With hydrogenchloride In ethanol; water 1.
Preparation of 6-bromopyridine-3-amine
To a solution of 2-bromo-5-nitropyridine (64 g, 0.317 mol)/ethanol (1 L) was successively added Fe powder (88 g, 1.571 mmol), concentrated hydrochloric acid (61 mL) and water (287 mL).
The reaction mixture was reacted under reflux for 5 h.
The reaction mixture was cooled and filtered.
The filtrate was concentrated and adjusted with a sodium bicarbonate solution to pH≈7-8, and re-filtered.
The resulting filtrate was extracted with dichlormethane.
The organic phase was dried with anhydrous sodium sulfate, and concentrated in a reduced pressure to produce 40.5 g of the title compound as a pale-yellow solid in a yield of 74.4percent.
74.4% With hydrogenchloride; iron In ethanol; water for 5 h; Reflux 1. Preparation of 6-bromopyridine-3-amine To a solution of 2-bromo-5-nitropyridine (64g, 0.317mol)/ethanol (1L) was successively added Fe powder (88g, 1.571mmol), concentrated hydrochloric acid (61mL) and water (287mL). The reaction mixture was reacted under reflux for 5h. The reaction mixture was cooled and filtered. The filtrate was concentrated and adjusted with a sodium bicarbonate solution to pH≈7-8, and re-filtered. The resulting filtrate was extracted with dichlormethane. The organic phase was dried with anhydrous sodium sulfate, and concentrated in a reduced pressure to produce 40.5g of the title compound as a pale-yellow solid in a yield of 74.4percent.
73% With iron; ammonium chloride In methanol; water at 50℃; for 6 h; 2-Bromo-5-nitro-pyridine (202 g, 1.0 mol) was dissolved in methanol (2.0 L), and a saturated aqueous ammonium chloride solution (2.0 L) was added thereto, followed by stirring at 50° C. Then, iron (224 g, 4.0 mol) was slowly added thereto, followed by stirring at 50° C. for 6 hours. The reaction solution was cooled to room temperature and then filtered, followed by washing with ethyl acetate. The filtrate was diluted with water, followed by extraction with ethyl acetate (1.0 L×6). The extraction liquids were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (2.0 L) and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain the title compound (126 g, 73percent). [1152] 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=2.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.90 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.50 (s, 2H)
73% With iron; ammonium chloride In methanol; water at 50℃; for 6 h; (Step 1) 6-Bromopyridin-3-amine (0221) (0222) 2-Bromo-5-nitro-pyridine (202 g, 1.0 mol) was dissolved in methanol (2.0 L), a saturated aqueous solution of ammonium chloride (2.0 L) was added thereto, the resulting mixture was stirred at 50° C., then iron (224 g, 4.0 mol) was slowly added thereto, and the resulting mixture was stirred at 50° C. for 6 hours. The reaction solution was cooled to room temperature and then filtered and washed with ethyl acetate. The filtrate was diluted with water and then extracted with ethyl acetate (1.0 L×6). The extracts were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (2.0 L) and a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the title compound (126 g, 73percent). (0223) 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=2.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.90 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.50 (s, 2H)
72% With 5%-palladium/activated carbon; hydrogen; sodium sulfate In tetrahydrofuran at 37℃; for 20 h; 0.282 g of 5percent Pd / C and lOmmol of anhydrous sodium sulfate were added to a 100 mL round bottom flask containing 20 mmol of 5-nitro-2-bromopyridine in 40 ml of tetrahydrofuran, then hydrogen was introduced, heated to 37 ° C and stirred 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, suction filtered, steamed and subjected to column chromatography (eluent: dichloromethane / acetone, 10: 1 in volume ratio) and dried in vacuo to give 2.476 g of 5-amino- Bromopyridine in 72percent yield.
40.5g With hydrogenchloride; iron In ethanol; water for 5 h; Reflux Iron powder (88g, 1.571mmol), concentrated hydrochloric acid (61mL) and water (287mL) were sequentially added to a solution of 2-bromo-5-nitropyridine (64g, 0.317mol) in ethanol (1L).
The mixture was reacted under reflux for 5 h.
The reaction mixture was cooled, filtered and the filtrate was concentrated and then adjusted to approximately pH 7-8 with a saturated aqueous solution of sodium bicarbonate, filtered again, and the filtrate was extracted with 200mL of dichloromethane.
The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 40.5g of a pale yellow solid.
40.5 g With hydrogenchloride; iron In ethanol; water for 5 h; Reflux Iron powder (88 g, 1.571 mmol), concentrated hydrochloric acid (61 mL) and water (287 mL) were sequentially added to a solution of 2-bromo-5-nitropyridine (64 g, 0.317 mol) in ethanol (1 L).
The mixture was reacted under reflux for 5 h.
The reaction mixture was cooled, filtered and the filtrate was concentrated and then adjusted to approximately pH 7-8 with a saturated aqueous solution of sodium bicarbonate, filtered again, and the filtrate was extracted with 200 mL of dichloromethane.
The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 40.5 g of a pale yellow solid.

Reference: [1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 1, p. 51 - 54
[2] Green Chemistry, 2018, vol. 20, # 1, p. 130 - 135
[3] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9841 - 9844
[4] Patent: EP2886540, 2015, A1, . Location in patent: Paragraph 0143; 0144
[5] Patent: US2014/93505, 2014, A1, . Location in patent: Page/Page column
[6] Patent: EP2719697, 2014, A1, . Location in patent: Paragraph 0097
[7] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 1151-1152
[8] Patent: US2016/244451, 2016, A1, . Location in patent: Paragraph 0221; 0222; 0223
[9] Patent: CN103755744, 2016, B, . Location in patent: Paragraph 0068; 0069
[10] Chemische Berichte, 1935, vol. 68, p. 315,321
[11] Yakugaku Zasshi, 1951, vol. 71, p. 662,665[12] Chem.Abstr., 1952, p. 8109
[13] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
[14] Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6303 - 6306
[15] Patent: EP518636, 1992, A1,
[16] Patent: EP518636, 1992, A1,
[17] Patent: EP2781520, 2014, A1, . Location in patent: Paragraph 0102; 0103; 0186 - 0188
[18] Patent: US2015/166539, 2015, A1, . Location in patent: Paragraph 0242; 0243
  • 2
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YieldReaction ConditionsOperation in experiment
86% With sodium hydroxide In N,N-dimethyl-formamide 1.1a Synthesis of 5-amino-2-bromopyridine
Tin (II) chloride hydrate (0.78 g, 3.5 mmol) was added to a stirring solution of 5-nitro-2-bromopyridine (0.24 g, 1.2 mmol) in DMF (5 mL) at RT. After 2 h, 6 N NaOH (2 mL) was added and the suspension was stirred vigorously for 10 min.
The organics were extracted with diethyl ether (2*10 mL), washed with brine (2*10 mL) and dried (Na2SO4).
The filtered solution was then concentrated under reduced pressure to afford the desired product as a yellow oil (0.178 g, 86percent), which was used without further purification.
1.2 Rearrangement of nicotinic acids
Rearrangement of the corresponding nicotinic acids (III) (Scheme 3) using a modified Schmidt reaction, followed by deprotection of the aniline group generated the desired aminopyridines (IV) as the corresponding TFA salts.
Reference: [1] Patent: US2001/49444, 2001, A1,
[2] Patent: US6495550, 2002, B2,
[3] Patent: US2002/193597, 2002, A1,
  • 3
  • [ 4487-59-6 ]
  • [ 7439-89-6 ]
  • [ 13534-97-9 ]
Reference: [1] Patent: US6001849, 1999, A,
[2] Patent: US6133253, 2000, A,
[3] Patent: US6133253, 2000, A,
  • 4
  • [ 4487-59-6 ]
  • [ 15069-92-8 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
  • 5
  • [ 4487-59-6 ]
  • [ 24242-20-4 ]
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 1995, vol. 36, # 10, p. 933 - 945
[2] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
[3] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
  • 6
  • [ 4487-59-6 ]
  • [ 30766-11-1 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
  • 7
  • [ 4487-59-6 ]
  • [ 32046-43-8 ]
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 1995, vol. 36, # 10, p. 933 - 945
[2] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
  • 8
  • [ 4487-59-6 ]
  • [ 5418-51-9 ]
Reference: [1] Journal of Organic Chemistry, 1980, vol. 45, # 15, p. 3097 - 3100
  • 9
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  • [ 15862-36-9 ]
Reference: [1] Organic Process Research and Development, 2004, vol. 8, # 1, p. 62 - 71
  • 10
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  • [ 4487-59-6 ]
Reference: [1] Yakugaku Zasshi, 1951, vol. 71, p. 662,665[2] Chem.Abstr., 1952, p. 8109
[3] Journal of the American Chemical Society, 1955, vol. 77, p. 6053
[4] Chemische Berichte, 1935, vol. 68, p. 315,321
  • 11
  • [ 4214-76-0 ]
  • [ 4487-59-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5046 - 5050
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
[3] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
  • 12
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Reference: [1] Russian Journal of Organic Chemistry, 2010, vol. 46, # 12, p. 1830 - 1834
  • 13
  • [ 223463-14-7 ]
  • [ 109-04-6 ]
  • [ 4487-59-6 ]
  • [ 19755-53-4 ]
  • [ 16420-30-7 ]
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 9, p. 4402 - 4413
  • 14
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  • [ 29082-92-6 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
  • 15
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  • [ 35969-75-6 ]
Reference: [1] Patent: WO2009/141386, 2009, A1,
  • 16
  • [ 223463-14-7 ]
  • [ 109-04-6 ]
  • [ 4487-59-6 ]
  • [ 19755-53-4 ]
  • [ 16420-30-7 ]
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 9, p. 4402 - 4413
  • 17
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  • [ 100367-55-3 ]
YieldReaction ConditionsOperation in experiment
90.8% for 16 h; Reflux A mixture of 2-bromo-5-nitropyridine (12.0 g, 59.1 mmol, CAS No.: 4487-59-6) and copper (I) cyanide (7.94 g, 88.7 mmol) in N,N-dimethylformamide (50 mL) was heated under reflux for 16 hours. After being cooled down to room temperature, the reaction mixture was poured into water and then extracted with ethyl acetate (100 mL x 3). The combined organiclayer was washed with brine, and then dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford 8.0 g of 5-nitropyridine-2-carbonitrile (yield was 90.8percent).
40% at 100℃; for 2 h; Step A: 5-Nitropicolinonitrile (20) [00383] A mixture of 2-bromo-5-nitropyridine (19) (10 g, 50 mmol) and CuCN (8.9 g, 100 mmol) in DMF (25 mL) was stirred at 100°C for 2 h. The reaction mixture was then cooled to room temperature and diluted with DCM (200 mL). Solid was filtered; the filtrated was then concentrated and purified by silica gel column chromatography with petroleum ether/ ethyl acetate (3 : 1) to give the product (3 g, 40percent) as a yellow solid. LC-MS: (M + H)+ 150.0
Reference: [1] Patent: WO2015/22301, 2015, A1, . Location in patent: Page/Page column 27; 28
[2] Organic Process Research and Development, 2004, vol. 8, # 1, p. 62 - 71
[3] Journal of the American Chemical Society, [4] Journal of the American Chemical Society, 2009, vol. 131, p. 3342 - 3348
[5] Patent: WO2017/184547, 2017, A1, . Location in patent: Page/Page column 00383
[6] Patent: US6150379, 2000, A,
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Reference: [1] Patent: US5262415, 1993, A,
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
  • 19
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  • [ 143-33-9 ]
  • [ 544-92-3 ]
  • [ 100367-55-3 ]
YieldReaction ConditionsOperation in experiment
85% at 100 - 150℃; for 2.08333 h; Synthesis of compound E; Copper cyanide (I) (662 mg, 7.34 mmol) and sodium cyanide (I) (242 mg, 4.93 mmol) were dissolved in N,N-dimethylformamide (7.5 ml), and the solution was stirred at 150°C for 25 minutes. A solution of 2-bromo-5-nitropyridine (113 mg, 0.700 mmol) completely dissolved in N,N-dimethylformamide (2.5 ml) at 100°C was added to the solution, and the mixture was stirred with heating at 150°C for 100 minutes. The completion of the reaction was confirmed using a TLC plate (ethyl acetate:hexane = 1:3), and the reaction was terminated with 10 ml of an aqueous solution of 1 M monopotassium phosphate, followed by extraction with ethyl acetate (50 ml .x. 3). The ethyl acetate layer was washed with water (100 ml) and with saturated saline (100 ml). The resultant was dried over magnesium sulfate and filtered, followed by removal of a solvent by distillation under reduced pressure. The product was separated via flash column chromatography (ethyl acetate:hexane = 1:7 --> 1:3) to obtain a yellow, oil-like target compound E (624 mg, 4.19 mmol). Yield: 85percent 1H-NMR (300 MHz, CDCl3) δ: 9.54 (dd, 1H, J = 2.5, 0.7 Hz, Py-H), 8.68 (dd, 1H, J = 8.4, 2.5 Hz, Py-H), 7.98 (dd, 1H, J = 8.4, 0.7 Hz, Py-H)
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 8, p. 2400 - 2411
[2] Patent: EP2070908, 2009, A1, . Location in patent: Page/Page column 11-12
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  • [ 4487-59-6 ]
  • [ 544-92-3 ]
  • [ 100367-55-3 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 1, p. 18 - 25
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  • [ 100367-55-3 ]
YieldReaction ConditionsOperation in experiment
1935 g at 80 - 160℃; for 5.5 h; 1) first equipped with a mechanical stirrer 30L glass reactor was added 7616mL dimethylformamide and612.8gNaCN and 1680gCuCN configured as a cyanide solution,The oil bath was then heated to 142 ° C,Continue to cyanide solution was added at a temperature of 80 ° C,A solution of 2-bromo-5-nitropyridine in dimethylformamide,Among them, 2-bromo-5-nitropyridine and dimethylformamide were 2538.6g and 5077mL respectively,And add within 5min,After adding at 160 reaction temperature, the reaction was 5.5h.2) After the reaction is completed, the temperature is lowered to 125 DEG C, 5757.5g of KH2PO4 buffer consisting of KH2PO4 and 42.2L of water are added,Keep the temperature of the mixture at 80 ~ 85 ° C for 1 h and cool to room temperature.3) The reaction mixture in step 2) was filtered, and the filtrate and filter cake were separated: the filtrate was extracted with 10 L of ethyl acrylate 3Times; the same filter cake was filtered after beating with ethyl acrylate, the two combined organic phase, and concentrated to 20L with KH2PO4 slowThe solution was washed sequentially with 14 L of water; the washed buffer and the aqueous layer were extracted twice more with 5 L of ethyl acrylate, and the combined organic phases were concentratedThe yield was 1935 g of 2-cyano-5-nitropyridine as an orange solid with a purity of 97percent and a yield of 103.8percent.
Reference: [1] Patent: CN106810494, 2017, A, . Location in patent: Paragraph 0021; 0022; 0023
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  • [ 15862-36-9 ]
Reference: [1] Organic Process Research and Development, 2004, vol. 8, # 1, p. 62 - 71
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  • [ 934266-82-7 ]
Reference: [1] Yakugaku Zasshi, 1951, vol. 71, p. 662,665[2] Chem.Abstr., 1952, p. 8109
  • 24
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  • [ 30651-24-2 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With copper(II) cyanide In DMF (N,N-dimethyl-formamide)
The reported procedure from Oehlke, J.; Schroetter, E.; Dove, S.; Schick, H.; Niedrich, H. Phannazie 1983, 38, 591-596, was slightly modified. When N, [N-DIMETHYLFORMAMIDE] (DMF) was used as the solvent instead of dimethylsulfoxide (DMSO) in the substitution of 2-bromo- 5-nitropyridine by copper [(I)] cyanide, subsequent hydrolysis provided the described acid in an improved 70percent yield, typically used without any further purification.
Reference: [1] Patent: WO2004/14904, 2004, A1, . Location in patent: Page 53
[2] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
[3] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
[4] Patent: WO2009/141386, 2009, A1, . Location in patent: Page/Page column 89
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  • [ 544-92-3 ]
  • [ 30651-24-2 ]
Reference: [1] Patent: US2005/38078, 2005, A1, . Location in patent: Page/Page column 29-30
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1995, vol. 36, # 10, p. 933 - 945
  • 26
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  • [ 52023-68-4 ]
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 45, p. 5905 - 5909
  • 27
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  • [ 55338-73-3 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 1, p. 18 - 25
[2] Patent: WO2015/22301, 2015, A1,
[3] Patent: WO2017/184547, 2017, A1,
[4] Patent: CN106810494, 2017, A,
  • 28
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  • [ 30563-98-5 ]
Reference: [1] Patent: WO2009/141386, 2009, A1,
  • 29
  • [ 110-85-0 ]
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  • [ 82205-58-1 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1996, vol. 85, # 1, p. 79 - 84
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1857 - 1872
[3] Patent: WO2009/95773, 2009, A2, . Location in patent: Page/Page column 77-78
[4] Patent: US2004/9988, 2004, A1, . Location in patent: Page/Page column 10
[5] Patent: US2007/167413, 2007, A1, . Location in patent: Page/Page column 43
[6] Patent: WO2007/83182, 2007, A2, . Location in patent: Page/Page column 71-72
[7] Patent: WO2009/95773, 2009, A2, . Location in patent: Page/Page column 77-78
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Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 45, p. 5905 - 5909
  • 31
  • [ 109-01-3 ]
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  • [ 55403-34-4 ]
YieldReaction ConditionsOperation in experiment
99% for 1.5 h; Heating / reflux Intermediate 4l-Methyl-4-(5-nitro-2-pyridinyl)piperazineTo a solution of 2-bromo-5-nitropyridine (22.3 g, 110 mmol) in CH3CN (200 mL) was added JV-methylpiperazine (30.5 mL, 275 mmol) and the resulting mixture was heated with stirring to reflux. After 90 min, the reaction was cooled to room temperature and concentrated to dryness. The solids were partitioned between water and EtOAc. The organic layer was separated and washed with brine, dried (MgSO4), filtered and concentrated to dryness affording the title compound as a yellow solid (24.2 g, 99percent). LC-MS (ES) m/z = 223 [M+H]+.
Reference: [1] Patent: WO2008/147831, 2008, A1, . Location in patent: Page/Page column 17
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 12, p. 3507 - 3525
[3] Organic and Biomolecular Chemistry, 2017, vol. 15, # 38, p. 8009 - 8012
[4] Tetrahedron Letters, 2011, vol. 52, # 45, p. 5905 - 5909
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  • [ 36625-57-7 ]
Reference: [1] Patent: WO2009/141386, 2009, A1,
  • 33
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  • [ 145255-19-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 1, p. 18 - 25
  • 34
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  • [ 119285-07-3 ]
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 45, p. 5905 - 5909
[2] Patent: EP2773638, 2015, B1,
  • 35
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  • [ 57260-71-6 ]
  • [ 193902-78-2 ]
YieldReaction ConditionsOperation in experiment
93% With potassium carbonate In dimethyl sulfoxide at 50℃; for 3 h; 2-Bromo-5-nitro-pyridine (11.39 g, 56.1 mmol), tetrabutylammonium iodide (TBAI) (1.04 g, 0.05 mmol), potassium carbonate (8.53 g, 61.7 mmol) and piperazine-1-carboxylic acid tert-butyl ester (11.5 g, 61.7 mmol) were mixed together in DMSO (100 mL) and gently warmed to 50 C. for 3 hours and cooled to room temperature overnight. The reaction was diluted with EtOAc (200 mL), the salts were filtered and then the EtOAc was evaporated to leave the DMSO solution. This was diluted with water and a precipitate formed. This precipitate was filtered, washed with water, and then dried in an oven vacuum to give 4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.1 g, 93percent) as a light orange solid. 1H NMR (400 MHz, CDCl3) ppm 1.47 (s, 9H), 3.55 (m, 4H), 3.75 (m, 4H), 6.55 (d, J=9.3 Hz, 1H), 8.21 (dd, J=9.5, 2.7 Hz, 1H), 9.03 (d, J=2.7 Hz, 1H). 4-(5-Nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.0 g, 51.9 mmol) was dissolved in THF (400 mL), RaNi (4 g) added and placed under a H2 atmosphere at 50 psi for 5 h. The catalyst was removed by filtration through celite and the solvent evaporated in vacuo to give 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (14.5 g, 100percent). 1H NMR (400 MHz, CDCl3) ppm 1.46 (s, 9H), 3.31 (m, 6H), 3.53 (m, 4H), 6.56 (d, J=8.8 Hz, 1H), 6.98 (dd, J=8.8, 2.9 Hz, 1H), 7.78 (dd, J=2.9, 0.7 Hz, 1H). m/z 279.1 (M+1).
71% With potassium carbonate In water at 150℃; for 0.25 h; Microwave irradiation In a 5 mL glass microwave tube were placed 2-bromo-5-nitro pyridine 1 (1015 mg, 5 mmol), 1-Boc-piperazine 2a (930 mg, 5 mmol), K2CO3 (690 mg, 5 mmol), H2O (3 mL) and a magnetic stir bar. The vessel was sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 300 W initial was used, the temperature being ramped from rt to 150 °C. Once 150 °C was reached, the reaction mixture was held at this temperature for 15 min. Thereafter the mixture was allowed to cool to rt, extracted with ethyl acetate (15 mL) and washed with water (10 mL) then dried over MgSO4. After filtration, the solvent was evaporated to afford a yellow solid 1100 mg (71percent) yield. 1H NMR CDCl3 δ = 9.03 (1H, s), 8.18 (1H, d, J = 9.1 Hz), 6.53 (1H, d, J = 9.5 Hz), 3.77-3.52 (8H, m), 1.44 (9H, s). 13C NMR CDCl3 δ = 164.2, 154.7, 145.3, 135.0, 133.2, 105.0, 79.8, 52.9 (2C), 46.0 (2C), 28.4 (3C).
70% With caesium carbonate In toluene at 20 - 80℃; for 1.25 - 2.25 h; BINAP [[ (R)-2,] 2'-Bis [(DIPHENYLPHOSPHINO)-1,] [1APOS;-BINAPHTHYL]] (2.5 g, 3.94088 mmoles) and tris (dibenzylidene acetone) dipalladium (o) (7.2 g, 7.88177 mmoles) were taken in dry toluene (400 ml) and stirred under argon atmosphere at room temperature for 15 minutes. 2-Bromo-5-nitro-pyridine (40 g, 197.044 mmoles) was dissolved in toluene (200 ml) and added to the reaction mixture followed by N-t-butoxycarbonyl piperazine (44 g, 236.45 mmoles). To this cesium carbonate (90 g, [275,] 862 mmoles) was added at room temperature under argon atmosphere. The reaction mixture was heated to [80 °C] for 1-2 hours under argon atmosphere and was cooled to RT and filtered through celite. Washed the residue thoroughly with ethylacetate. The combined filtrates were washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel column using dichloromethane and methanol as eluent to yield the title compound (42.4 g, yield 70percent).
54% for 2.5 h; Reflux Example 197a
tert-Butyl 4-(5-Nitropyridin-2-yl)piperazine-1-carboxylate 197a
A mixture of 2-bromo-5-nitropyridine (5.0 g, 24.6 mmol), tert-butyl piperazine-1-carboxylate (13.8 g, 74.2 mmol), acetonitrile (150 mL) was stirred at reflux for 2.5 h.
After the reaction was completed, the solvent was removed under reduced pressure to afford 197a as a yellow solid (4.1 g, 54percent). MS-ESI: [M+H]+ 309.

Reference: [1] Patent: US2005/182078, 2005, A1, . Location in patent: Page/Page column 9; 12
[2] Tetrahedron Letters, 2011, vol. 52, # 45, p. 5905 - 5909
[3] Patent: WO2004/9587, 2004, A1, . Location in patent: Page 36
[4] Patent: EP2773638, 2015, B1, . Location in patent: Paragraph 0753; 0754
[5] Patent: US2004/9988, 2004, A1, . Location in patent: Page/Page column 10
  • 36
  • [ 4487-59-6 ]
  • [ 25487-66-5 ]
  • [ 864075-95-6 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate In ethanol; water; toluene for 48 h; Heating / reflux 2-Bromo-5-nitropyridine (1.96g, 9. 6mmol) and 3- carboxybenzeneboronic acid (1.8g, 10. 8mmol, l. lequiv. ) were dissolved in a mixture of toluene (40mL), ethanol (40mL) and water (5mL) and potassium carbonate (4.1g, 29.3mmol, 3. 0equiv.) was added. The flask was purged with nitrogen gas then palladium tetrakis (triphenylphosphine) (0.2g) was added and the mixture heated at reflux for 48 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (lOOmL) and extracted with water (3 x 50mL). The aqueous extracts were combined and washed with dichloromethane (3 x 50mL). The aqueous fraction was acidified (pH 1-2) with concentrated hydrochloric acid to give an off white precipitate, which was collected on a filter and dried under vacuum to give a white solid 18,2. 132g (91percent). 1H-NMR (d6-DMSO) 8 13.21 (1H, bs, CO2H), 9.46 (1H, d, J = 2.7Hz, H- 6'), 8.75 (1H, dd, J= 1. 6Hz, H-2), 8.66 (1H, dd, J = 2.7, 8.8Hz, H-4'), 8.42 (1H, ddd, J = 1.2, 1.9, 7.9Hz, H-6), 8.33 (1H, dd, J = 8.8Hz, H-3'), 8.10 (1H, m, H-4), 7.69 (1H, dd, J = 7.8Hz, H-5); 13C NMR (d6-DMSO) 8 166.8, 159.9, 144.9 (CH), 143.3, 136.9, 132.8 (CH), 131.7, 131.6 (CH), 131.3 (CH), 129.5 (CH), 128.2 (CH), 120.8 (CH); LCMS RT = 3.00 min, (M--l) = 243.
Reference: [1] Patent: WO2005/85177, 2005, A2, . Location in patent: Page/Page column 50-51
  • 37
  • [ 4487-59-6 ]
  • [ 170850-45-0 ]
Reference: [1] Tetrahedron, 2012, vol. 68, # 45, p. 9272 - 9277
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