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[ CAS No. 15128-82-2 ]

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Chemical Structure| 15128-82-2
Chemical Structure| 15128-82-2
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CAS No. :15128-82-2 MDL No. :MFCD00006258
Formula : C5H4N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :140.10 g/mol Pubchem ID :27057
Synonyms :

Safety of [ 15128-82-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 15128-82-2 ]

  • Upstream synthesis route of [ 15128-82-2 ]
  • Downstream synthetic route of [ 15128-82-2 ]

[ 15128-82-2 ] Synthesis Path-Upstream   1~20

  • 1
  • [ 15128-82-2 ]
  • [ 6636-78-8 ]
Reference: [1] Pharmaceutical Bulletin, 1957, vol. 5, p. 350,352
  • 2
  • [ 15128-82-2 ]
  • [ 6602-32-0 ]
Reference: [1] Pharmaceutical Bulletin, 1957, vol. 5, p. 350,352
  • 3
  • [ 15128-82-2 ]
  • [ 16867-03-1 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5 h;
Stage #2: With sodium hydrogencarbonate In water
General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 37, p. 3646 - 3649
[2] Journal of the Chemical Society, <1957> 4625,
[3] Pharmaceutical Bulletin, 1957, vol. 5, p. 350,352
[4] Biochemical Journal, 1950, vol. 46, p. 506
[5] Patent: US1889303, 1930, ,
[6] Green Chemistry, 2016, vol. 18, # 8, p. 2435 - 2442
[7] Applied Catalysis A: General, 2016, vol. 525, p. 85 - 93
[8] Patent: US1889303, 1930, ,
  • 4
  • [ 15128-82-2 ]
  • [ 52092-47-4 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1958, vol. 77, p. 92,95
[2] Recueil des Travaux Chimiques des Pays-Bas, 1958, vol. 77, p. 92,95
  • 5
  • [ 74037-50-6 ]
  • [ 15128-82-2 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 4, p. 577 - 579
  • 6
  • [ 109-00-2 ]
  • [ 15128-82-2 ]
Reference: [1] Roczniki Chemii, 1936, vol. 16, p. 502,507[2] Chem. Zentralbl., 1937, vol. 108, # I, p. 3634
[3] Pharmaceutical Bulletin, 1957, vol. 5, p. 350,352
[4] Patent: US1889303, 1930, ,
  • 7
  • [ 15128-82-2 ]
  • [ 201230-82-2 ]
  • [ 60832-72-6 ]
Reference: [1] European Journal of Organic Chemistry, 2005, # 8, p. 1675 - 1679
  • 8
  • [ 15128-82-2 ]
  • [ 20348-09-8 ]
Reference: [1] Tetrahedron, 2011, vol. 67, # 6, p. 1187 - 1192
  • 9
  • [ 15128-82-2 ]
  • [ 39968-33-7 ]
Reference: [1] Tetrahedron, 1996, vol. 52, # 38, p. 12357 - 12372
[2] Synthesis, 1996, # 3, p. 383 - 387
  • 10
  • [ 15128-82-2 ]
  • [ 152170-30-4 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1993, vol. 130, # 3, p. 395 - 404
  • 11
  • [ 15128-82-2 ]
  • [ 152170-29-1 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1993, vol. 130, # 3, p. 395 - 404
  • 12
  • [ 15128-82-2 ]
  • [ 443956-08-9 ]
YieldReaction ConditionsOperation in experiment
96% With bromine; sodium methylate In methanol at 0 - 20℃; for 1 h; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification: MS (ES) m/z219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Stage #3: With acetic acid In methanol
Preparation 3; Preparation of 3-Oxo-3,4-dihydro-2/-/-pyridoF3,2-d1f 1 ,41oxazine-6-carboxaldehvde; (a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml_) and a solution of 25percent sodium methoxide in methanol (33 ml_, 0.13 mole) was added at - room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 ml_, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 ml_). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification: MS (ES) m/z219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Stage #3: With acetic acid In methanol
Preparation 3; Preparation of 3-Oxo-3.4-dihydro-2H-pyrido[3,2-biπ ,41oxazine-6-carboxaldehyde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml_) and a solution of 25percent sodium methoxide in methanol (33 ml_, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 ml_, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 ml_). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. EPO <DP n="26"/>MS (ES) m/z219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Stage #3: With acetic acid In methanol
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification.MS (ES) m/z219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 0 - 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Stage #3: With acetic acid In methanol
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 °C, and EPO <DP n="24"/>bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification: MS (ES) m/z219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Preparation 3; Preparation of 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0° C. for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) m/z219.0 (M+H)+.; Preparation 6; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0° C. for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) m/z219.0 (M+H)30 .
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml) and a solution of 25percent sodium methoxide in methanol (33 ml, 0.13 mol) was added at room temperature. The mixture was stirred for 30 minutes, then cooled to 0 °C, and bromine (7.2 ml, 0.14 mol) was added slowly. The reaction was then stirred at 0 °C for 30 minutes, then was quenched with glacial AcOH (2.5 ml). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (+ve ion electrospray) m/z 219 (MH+).
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 [ML)] and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to [0 °C,] and bromine (7. [2] mL, 0.14 mole) was added slowly. The reaction was then stirred at [0 °C] for 30 min, then was quenched with glacial [ACOH] (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) [NIEZ 219.] 0 [(M + H)] +.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Stage #3: With acetic acid In methanol
3-Hydroxy-2-nitropyridine (20 g, 0.143 mol) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mol) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 degree;C, and bromine (7.2 mL, 0.14 mol) was added slowly. The reaction was then stirred at 0 degree;C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) m/z 219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml) and a solution of 25percent sodium methoxide in methanol (33 ml, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 °C, and bromine (7.2 ml, 0.14 mole) was added slowly. The reaction was then stirred at 0 °C for 30 min, then was quenched with glacial AcOH (2.5 ml). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) m/z 219.0 (M + H) +.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Stage #3: With acetic acid In methanol
Preparation 16; Preparation of 3-Oxo-3,4-dihvdro-2/-/-pyridor3,2-jb1H ,41oxazine-6-carboxaldehyde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 °C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 ml_). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) m/z 219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Stage #3: With acetic acid In methanol
Preparation 10; Preparation of 3-Oxo-3.4-dihvdro-2H-pvrido[3.2-foiri ,41oxazine-6-carboxalde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml)and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added atroom temperature. The mixture was stirred for 30 min, then was cooled to 0 °C, andbromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 °C for 30mm, irien was quenuneu wiui yiauitil AcOH (2.5 mL). The solvent was removed in vacuato afford material (30 g, 96percent), which was used without further purification.MS(ES)m/z219.0(M + H)+.; Preparation 11; Preparation of 7-chloro-3-oxo-3,4-dihydro-2/-/-1.4-benzoxazine-6-carbaldehyde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml)and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added atroom temperature. The mixture was stirred for 30 min, then was cooled to 0 °C, andbromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 °C for 30min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuato afford material (30 g, 96percent), which was used without further purification.MS(ES)m/z219.0(M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Preparation 5; Preparation of 3-Oxo-3.4-dihvdro-2H-pvridof3.2-/?in ,41oxazine-6-carboxaldehvde; (a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 °C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 °C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification: MS (ES) m/z 219.0 (M + H)+.
96% With bromine; sodium methylate In methanol at 0℃; for 0.5 h; a) 2-Bromo-5-hydroxy-6-nitropyridine3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) m/z219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml_) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) m/z219.0 (M + H)+.
a. 2-bromo-5-hydroxy-6-nitropyridine 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml_) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C1 and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 °C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification. MS (ES) m/z 219.0 (M + H)+.
96%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 0℃; for 0.5 h;
Stage #3: With acetic acid In methanol
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25percent sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, and then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96percent), which was used without further purification: MS (ES) m/z219.0 (M + H)+
86.4% With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 12 h; 3-Hydroxy-2-nitropyridine (50 g, 357 mmol) was dissolved in 900 mL of N, N-dimethylformamide. N-bromosuccinimide (82.57 g, 464 mmol) was slowly added thereto and stirred at room temperature for 12 hours. After the reaction was completed, the solution was concentrated using a rotary evaporator, and then extracted twice with distilled water and dichloromethane.The precipitate was formed using methyl alcohol and distilled water and filtered to obtain a mixture of compound 1 and dibrominated compound (67.5 g, Y = 86.4percent) in an 8: 2 ratio.
62% With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 3 h; (Example 2 Synthesis of Compounds I-113 and 1-144) [Show Image]Step 1 A solution of 2-nitropyridin-3-ol (6) (16.0 g, 114 mmol) in dimethylformamide (120 mL) was cooled to 0°C, and then N-bromosuccinimide (26.4 g, 1.48 mmol) was gradually added thereto. The solution was then stirred at 0 °C for 1 hour, and at room temperature for another 2 hours. The reaction solution was concentrated in vacuo, and then the residue was washed with diethyl ether. The filtrate was poured to aqueous saturated sodium bicarbonate, followed by extraction with diethyl ether. The organic layer was washed sequentially with water and saturated brine, then dried with anhydrous magnesium sulfate, and concentrated in vacuo to yield the subject compound (7) (15.5 g, 62percent) as a white powder.
54% With tin(II) bromide; sodium hydroxide In water at 3.3 - 20℃; for 0.966667 h; A solution of 3-hydroxy-2-nitropyridine (176.0 g, 1.256 mol) in aqueous sodiumhydroxide (74.0 mL of 50percent NaOH in 1.94 L water, 1.40 mol) was cooled at 3.3 °C whiledibromantin (198.5 g, 0.694 mol) was added portion-wise over 58 minutes maintaining reaction temperature at or below 4 °C. The reaction mixture was then allowed to warm to room temperature overnight. The reaction was quenched with acetic acid (80.0 mL, 1.34 mol), and the resulting slurry was stirred at room temperature for 4 h. The solids werecollected by filtration, washed with water (3 x 300 mL), and then vacuum-dried (35°C) overnight to give 148.3 g (54percent) of 2-bromo-5-hydroxy-6-nitropyridine as a yellow solid with a purity of 97.8percent (LC).
54.1% With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; A solution of 2-nitropyridin-3-ol (15 g, 104 mmol) in DMF (189 mL) was cooled to 0°C then N- bromosuccinimide (24 g, 135 mmol) was added gradually over 25 minutes. The solution was stirred at 0°C for an additional 15 minutes and then the mixture was allowed to warm to RT, and stirred over night. The reaction mixture was concentrated in vacuo and purified by column chromatography using 100percent CH2CI2 to afford 6-bromo-2-nitro-pyridin-3-ol (13.67 g, 56.2 mmol, 54.1 percent yield) as a yellow solid. MS ES+ (m/z): 219.1 [(M+H)+].
53%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h; Inert atmosphere
Stage #2: With bromine In methanol at 0 - 5℃; for 4 h; Inert atmosphere
Compound I-1 (5 g, 35.7 mmol) was added to a clean and dry reaction flask,Dissolved in 50 mL of methanol,After replacing the nitrogen three times,Sodium methoxide (2.89 g, 53.5 mmol)In methanol (15 mL) was added dropwise to the reaction system,The reaction was stirred at room temperature for 30 min.The reaction was then cooled to 0 ° C,Bromine (6.3 g, 39.4 mmol) was added dropwise,The temperature of the reaction system was controlled at 0-5 ° CUnder the conditions of reaction 4h;(CH2Cl2: CH3OH = 25: 1), the reaction was quenched with a small amount of 10percent aqueous sodium sulfite solution, the reaction system was cooled to -15C, and the yellow solid was stirred,After filtration, the filter cake was washed with ice methanol (2 x 5 mL), dried,A yellow solid was the target product I-2 (4.2 g, 53percent).
53%
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h; Inert atmosphere
Stage #2: at 0℃; Inert atmosphere
Under an atmosphere of nitrogen, a solution of CH3ONa (2.89 g,53.5 mmol) in CH3OH (15 mL) was added dropwise to a solution of2-nitropyridin-3-ol (16) (5 g, 35.7 mmol) in CH3OH (50 mL) and themixture was stirred at RT for 30 min. After the reaction systemcooling to 0 C, Br2 (6.3 g, 39.4 mmol) was added dropwise withstirring. After 16 was consumed, the mixture was quenched byadding a solution of 10percent Na2SO3 and then cooled to 15 C. Yellowsolid was precipitated, filtered and washed with cold CH3OH. Thetitle compound was obtained as a yellow solid (4.2 g, 53percent). 1H NMR(400 MHz, DMSO) d 7.85 (d, J 8.64 Hz, 1H), 7.66 (d, J 8.64 Hz,1H); MS (M H): m/z 216.97.
28%
Stage #1: With bromine; sodium methylate In methanol at 0℃; for 0.5 h;
Stage #2: With acetic acid In methanol at 0℃; for 0.166667 h;
At 0 °C, Br2 was slowly added to a mixture of 2-nitropyridin-3-ol ( 1 ; 80.0 g, 570 mmol) and NaOCH3 (30.8 g, 570 mmol) in methanol (600 mL) and stirred at this temperature for 30 m in. AcOH (1.5 mL) was added to the mixture and stirred again for 1 0 min. The crude reaction mixture was then concentrated in vacuo to afford a yellow solid, which was triturated in mixed petroleum ether/EtOAc to give 6-bromo-2-nitropyridin-3-ol (2; 35.0 g, 28percent). M S (ESI) calcd for C5H3BrN203 (m/z): 2 17.93.
22.00 g
Stage #1: at 15℃; for 0.5 h;
Stage #2: at 0 - 15℃; for 16 h;
To a solution of A-25 (10 g, 71.38 mmol) in methanol (200 mL) was added CH3ONa (3.85 g, 71.38 mmol) slowly at 15 °C. The resulting solution was stirred at 15 °C for 30 min. Then Br2 (11.41 g, 71.38 mmol) was added to the solution dropwise 0 °C and the mixture was stirred at 15 °C for 16 hours. The reaction solution was quenched with glacial AcOH (1.25 mL) and concentrated to give the crude product of A-26 (22.00 g, crude) as a solid. The crude product was used in the next step without further purification. LCMS Rt = 0.54 mins using Method B, MS ESI calcd. for C5H4BrN203 [M+H]+ 218.9, found 219.1.

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[18] Patent: EP2341052, 2011, A1, . Location in patent: Page/Page column 35
[19] Patent: WO2017/87965, 2017, A1, . Location in patent: Page/Page column 24
[20] Patent: WO2017/97728, 2017, A1, . Location in patent: Page/Page column 151
[21] Patent: CN107188900, 2017, A, . Location in patent: Page/Page column 0039; 0040; 0041
[22] European Journal of Medicinal Chemistry, 2018, vol. 159, p. 255 - 266
[23] Patent: WO2011/59839, 2011, A1, . Location in patent: Page/Page column 64
[24] Patent: WO2007/118130, 2007, A2, . Location in patent: Page/Page column 30
[25] Journal of Medicinal Chemistry, 2010, vol. 53, # 3, p. 1222 - 1237
[26] Patent: US2006/223810, 2006, A1, . Location in patent: Page/Page column 24-25
[27] Patent: WO2013/134562, 2013, A1, . Location in patent: Paragraph 00218
[28] Patent: WO2013/3383, 2013, A1, . Location in patent: Page/Page column 78-79
[29] Patent: WO2014/6402, 2014, A1, . Location in patent: Page/Page column 85
[30] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 609 - 614
[31] Patent: US2016/95858, 2016, A1, . Location in patent: Paragraph 5359; 5360
[32] Patent: WO2016/123146, 2016, A1, . Location in patent: Paragraph 0075-0076
[33] Patent: WO2017/199265, 2017, A1, . Location in patent: Paragraph 000132
[34] Patent: WO2018/148745, 2018, A1, . Location in patent: Page/Page column 104
  • 13
  • [ 15128-82-2 ]
  • [ 337463-88-4 ]
Reference: [1] Patent: EP2341052, 2011, A1,
[2] Patent: WO2013/3383, 2013, A1,
[3] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 609 - 614
[4] Patent: WO2016/123146, 2016, A1,
[5] Patent: WO2017/199265, 2017, A1,
  • 14
  • [ 15128-82-2 ]
  • [ 877397-65-4 ]
  • [ 877397-70-1 ]
YieldReaction ConditionsOperation in experiment
88.3% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 13 h; 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine
3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere.
The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, 1.65 mmol) was added at 0° C.
The mixture was stirred for an additional 12 h.
The reaction mixture was evaporated under vacuum to give an oil.
The residue was purified by flash chromatography (eluding with 20-->25percent EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3percent yield); MS (APCI) (M+H)+ 331; SFC-MS: 99.5percent ee. 1H NMR (400 MHz, chloroform-D) δ ppm 1.85 (d, J=6.6 Hz, 3H) 6.10 (q, J=6.6 Hz, 1H) 7.04-7.13 (m, 1H) 7.21 (dd, J=8.5, 1.14 Hz, 1H) 7.30 (dd, J=9.0, 4.9 Hz, 1H) 7.37 (dd, J=8.6, 4.6 Hz, 1H) 8.04 (dd, J=4.6, 1.3 Hz, 1H).
88.3% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 13 h; 3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere. The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, i.65 mmol) was added at 0°C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated under vacuum to give an oil. The residue was purified by flash chromatography (eluting with 20->25percent EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3percent yield); MS (APCI) (M+H)+ 331; SFC-MS: 99.5percent ee. 1H NMR (400 MHz, chloroform-D) 8 ppm 1.85 (d, J=6.6 Hz, 3 H) 6.10 (q, J=6.6 Hz, 1 H) 7.04 -7.13 (m, 1 H) 7.21 (dd, J=8.5, 1.14 Hz, 1 H) 7.30 (dd, ^=9.0, 4.9 Hz, 1 H) 7.37 (dd, J=Q.6, 4.6 Hz, 1 H) 8.04 (dd, Jt4.6, 1.3 Hz, 1 H).
80.4% With triphenylphosphine; diisopropyl azodicarboxylate In toluene at -20 - 20℃; for 1 h; Inert atmosphere The (S) - 1 - (2,6-dichloro-3-fluoro phenyl) ethanol (42.80g, 204 . 7mmol), 3-hydroxy-2-nitro-pyridine (28.97g, 206 . 8mmol), triphenylphosphine (61.22g, 233 . 4mmol) in 300 ml toluene in, N2protection, using ethanol does the ice-bath lower the temperature to -20 °C. Dropwise DIAD (48.44g, 239 . 6mmol) toluene (50 ml) solution. Is omitted, to eliminate outside bath, the natural reaction system rose to room temperature, stirring 1 hour. TLC confirmed the completion of reaction, adding 3.7 ml water, stirring overnight. The salt bath is then used to lower the temperature to -10 °C reaction system, separating solid. Filtering, the filter cake is washed with the toluene washes, concentrating the filtrate to the stem, by adding 150 ml ethanol, concentrated again, two times repeatedly, shall be II-1 crude product (110g). Ethanol is added to the crude 3.4L, beating 4 °C 1 hour. Filtering, with 4 °C ethanol washing, the filter cake reduced-pressure drying, be II-1 (54.48g, 80.4percent), white solid.
80% With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 2 h; 300 g of TM2, 205 g of SM2 and 540 g of triphenylphosphine were dissolved in 2 L of THF and 361 g of DEAD was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for two hours, and the reaction was complete by TLC (PE / EA = 3: 1).The ethyl acetate layer was dried and concentrated to 2 ° C to 0 ° C to precipitate a large amount of solid which was collected by filtration and the filtrate was concentrated to a final concentration of ethyl acetate. 1L. After cooling, the solid was separated. The solids were collected by filtration twice, washed with PE / EA = 5: 1 and filtered to remove solids (about 500 g), and the filtrate was evaporated to remove the solvent.Column chromatography gave 400 g of TM3 (pale yellow solid, eluent PE / EA = 7: 1) in 80percent yield.
61%
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 12 h;
Step 1:
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethyoxyl)-2-nitropyridine
(S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) was dissolved in anhydrous tetrahydrofuran (200 mL), and then 3-hydroxy-2-nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol) were subsequently added under a nitrogen atmosphere.
The reaction liquid was stirred at room temperature for 1 hour.
After the reaction was cooled to 0°C, DIAD (40 mL, 0.15 mol) was added and the resultant was stirred for 12 hours.
The solvent was evaporated, and the crude oil product was purified by silica gel column chromatography to give (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethyoxyl)-2-nitropyridine (20.2 g, 61percent yield).
61%
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 12 h;
(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) was dissolved in anhydrous tetrahydrofuran (200 mL), and then 3-hydroxy-2-nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol) were subsequently added under a nitrogen atmosphere.
The reaction mixture was stirred at room temperature for 1 hour, cooled to 0°C, diisopropyl azodicarboxylate (40 mL, 0.15 mol) was added and the mixture was stirred for 12 hours at 0°C.
After evaporating the solvent, the resulting oil product was purified by silica gel column chromatography to give (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxyl)-2-nitropyridine (20.2 g, 61percent yield).
61%
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 12 h;
(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) was dissolved in 200 mL anhydrous tetrahydofuran, to which 3-hydroxy-2-nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol) were sequentially added under a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 1 hour, cooled to 0° C. and diisopropyl azodicarboxylate (40 mL, 0.15 mol) was added dropwise.
After the addition was complete, stirring was continued at 0° C. for 12 hours.
The solvent was distilled off to obtain an oily material, which was separated by silica gel column chromatography, to give (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (20.2 g). Yield: 61percent.
2.5 kg
Stage #1: With triphenylphosphine In toluene at -20℃; for 3 h; Inert atmosphere; Large scale
Stage #2: With di-isopropyl azodicarboxylate In toluene at -20 - 25℃; for 2 h; Large scale
1.82 kg of compound (CZT-2),1.23 kg 3-hydroxy-2-nitropyridinewith2.60 kg of triphenylphosphine dissolvedIn 15.0 liters of dry toluene,Nitrogen protection,Cool to -20 degrees.In 3 hours slowly joined2.04 kg DIAD 2.62 litersToluene solution,Keep the system temperature between -20 degrees and -10 degrees,After the addition was complete, the temperature was raised to 25 ° C for 2 hours.Add 0.16 liters of water to quench the reaction,Cooled to -5 degrees,filter,The filtrate was concentrated under reduced pressure.Recrystallization from 7.5 liters of absolute ethanol,To obtain 2.50 kg of compound (CZT-3) in a yield of 85percent

Reference: [1] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 20
[2] Patent: WO2006/21886, 2006, A1, . Location in patent: Page/Page column 51
[3] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1018 - 1026
[4] Patent: CN105348265, 2016, A, . Location in patent: Paragraph 0056; 0057; 0058
[5] Patent: CN103664896, 2016, B, . Location in patent: Paragraph 0108; 0109
[6] Patent: EP2952510, 2015, A1, . Location in patent: Paragraph 0112; 0113
[7] Patent: EP3176160, 2017, A1, . Location in patent: Paragraph 0041
[8] Patent: US2018/244649, 2018, A1, . Location in patent: Paragraph 0152; 0153; 0154
[9] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[10] Patent: CN106317024, 2017, A, . Location in patent: Paragraph 0049; 0050
[11] Patent: CN107417603, 2017, A, . Location in patent: Paragraph 0021
  • 15
  • [ 15128-82-2 ]
  • [ 330156-50-8 ]
  • [ 877397-70-1 ]
YieldReaction ConditionsOperation in experiment
88.3%
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 1 h;
Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 12 h;
3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere. The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, 1.65 mmol) was added at 0°C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated under vacuum to give an oil. The residue was purified by flash chromatography (eluting with 20->25percent EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3percent yield); MS (APCI) (M+H)+ 331; SFC-MS: 99.5percent ee. 1H NMR (400 MHz, chlorqform-D) 5 ppm 1.85 (d, ^6.6 Hz, 3 H) 6.10 (q, J=6.6 Hz, 1 H) 7.04 -7.13 (m, 1 H) 7.21 (dd, J=8.5, 1.14 Hz, 1 H) 7.30 (dd, J=9.0, 4.9 Hz, 1 H) 7.37 (dd, J=8.6, 4.6 Hz, 1 H) 8.04 (dd, J=4.6, 1.3Hz, 1 H).
Reference: [1] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 59
  • 16
  • [ 15128-82-2 ]
  • [ 877399-98-9 ]
  • [ 877397-70-1 ]
YieldReaction ConditionsOperation in experiment
92.1% With N-ethyl-N,N-diisopropylamine In 2-methyltetrahydrofuran for 4 h; Reflux The compound of formula (III) (25 g, 0.087 mol) was added to the reaction flask,2-nitro-3-hydroxypyridine (XII) (14 g, 0.1 mol) was added,DIPEA (33.7 g, 0.26 mol) and2-MeTHF (300 mL).The reaction was heated at reflux for 4 h. TLC indicated the reaction of the starting material was complete. The reaction solution was cooled to room temperature, filtered and the cake was used2-MeTHF (20 mL).The filtrate was washed successively with 1N HCl, 5percent NaHCO3 and saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 26.5 g of a yellow solid in a yield of 92.1percent
Reference: [1] Patent: CN105924431, 2016, A, . Location in patent: Paragraph 0128; 0129; 0130; 0131
  • 17
  • [ 15128-82-2 ]
  • [ 934758-27-7 ]
Reference: [1] Patent: CN107188900, 2017, A,
[2] Patent: WO2018/148745, 2018, A1,
[3] European Journal of Medicinal Chemistry, 2018, vol. 159, p. 255 - 266
  • 18
  • [ 15128-82-2 ]
  • [ 947249-13-0 ]
Reference: [1] Patent: WO2014/111496, 2014, A1,
[2] Patent: WO2015/91889, 2015, A1,
[3] Patent: US2015/175619, 2015, A1,
[4] Patent: WO2016/142310, 2016, A1,
  • 19
  • [ 15128-82-2 ]
  • [ 1206981-49-8 ]
Reference: [1] Patent: WO2014/111496, 2014, A1,
[2] Patent: WO2015/91889, 2015, A1,
[3] Patent: US2015/175619, 2015, A1,
  • 20
  • [ 15128-82-2 ]
  • [ 916737-77-4 ]
Reference: [1] Patent: WO2014/6402, 2014, A1,
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