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Product Details of [ 624-28-2 ]

CAS No. :624-28-2 MDL No. :MFCD00006221
Formula : C5H3Br2N Boiling Point : -
Linear Structure Formula :- InChI Key :ZHXUWDPHUQHFOV-UHFFFAOYSA-N
M.W : 236.89 Pubchem ID :69353
Synonyms :

Calculated chemistry of [ 624-28-2 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 39.64
TPSA : 12.89 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) : -5.92 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.03
Log Po/w (XLOGP3) : 2.57
Log Po/w (WLOGP) : 2.61
Log Po/w (MLOGP) : 2.01
Log Po/w (SILICOS-IT) : 2.8
Consensus Log Po/w : 2.4

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.48
Solubility : 0.0779 mg/ml ; 0.000329 mol/l
Class : Soluble
Log S (Ali) : -2.49
Solubility : 0.769 mg/ml ; 0.00325 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.74
Solubility : 0.0435 mg/ml ; 0.000184 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.85

Safety of [ 624-28-2 ]

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 [ 624-28-2 ]

* 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 [ 624-28-2 ]
  • Downstream synthetic route of [ 624-28-2 ]

[ 624-28-2 ] Synthesis Path-Upstream   1~130

  • 1
  • [ 624-28-2 ]
  • [ 223463-13-6 ]
YieldReaction ConditionsOperation in experiment
55% With hydrogen iodide; sodium iodide In water for 24 h; Reflux Aqueous HI (57 percent) was added to 2,5-dibromopyridine (12.60 g, 53.2 mmol) and Nal (11.40 g, 76 mmol). The resulting mixture was heated at reflux for 24 h, cooled and thendiluted with water (100 mL). The resulting mixture was basified with NaHCO3 and treated with Na2S2O4 until colourless. The mixture was extracted with DCM (5 x 60 mL) and the dried (Na2SO4) solvent removed under reduced pressure. The residue was collected by filtration and washed with Et20 (60 mL) and air dried to give the 5-bromo-2-iodopyridine (8.28 g, 55 percent) as a light grey powder.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4528 - 4532
[2] Chemical Communications, 2012, vol. 48, # 8, p. 1120 - 1122
[3] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[4] Journal of Organic Chemistry, 2001, vol. 66, # 2, p. 605 - 608
[5] Organic Letters, 2004, vol. 6, # 26, p. 4905 - 4907
[6] Synlett, 2002, # 2, p. 271 - 272
[7] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
[8] European Journal of Organic Chemistry, 2000, # 20, p. 3483 - 3487
[9] Patent: WO2018/127540, 2018, A1, . Location in patent: Page/Page column 20; 21
[10] Patent: US2001/53850, 2001, A1,
[11] Patent: US6822093, 2004, B2,
[12] Patent: US2003/135046, 2003, A1,
[13] Patent: US2005/234046, 2005, A1, . Location in patent: Page/Page column 73
  • 2
  • [ 624-28-2 ]
  • [ 73290-22-9 ]
  • [ 223463-13-6 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
  • 3
  • [ 624-28-2 ]
  • [ 73290-22-9 ]
  • [ 116195-81-4 ]
  • [ 223463-13-6 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
  • 4
  • [ 624-28-2 ]
  • [ 2294-76-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 11, p. 2863 - 2870
  • 5
  • [ 624-28-2 ]
  • [ 74-88-4 ]
  • [ 3510-66-5 ]
Reference: [1] Green Chemistry, 2011, vol. 13, # 5, p. 1110 - 1113
[2] Australian Journal of Chemistry, 2013, vol. 66, # 2, p. 199 - 207
  • 6
  • [ 624-28-2 ]
  • [ 107-21-1 ]
  • [ 1072-97-5 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 19, p. 3251 - 3254
  • 7
  • [ 624-28-2 ]
  • [ 13466-38-1 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
[2] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 70,73
  • 8
  • [ 624-28-2 ]
  • [ 16110-09-1 ]
YieldReaction ConditionsOperation in experiment
87% With trans-bis(glycinato)copper(II) monohydrate; tetramethlyammonium chloride In ethanol at 100℃; for 24 h; Schlenk technique; Inert atmosphere General procedure: A Schlenk tube was charged with catalyst 1 (10 mol percent), aryl (or heteroaryl) bromide (1.0 mmol), tetramethylammonium chloride (Me4NCl) (2.0 mmol), and EtOH (2.0 mL) under nitrogen atmosphere. The Schlenk tube was sealed with a Teflon valve, and then the reaction mixture was stirred at 100 °C for a period as mentioned in Table 2 (the reaction progress was monitored by GC analysis). After completion of the reaction, the solvent was removed under reduced pressure. The residue obtained was purified via silica gel chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to afford aryl chlorides. The yield of the products was determined by high resolution GC–MS analysis and the identity of the products was confirmed by comparing their physical and spectral data with the known compounds.
Reference: [1] Applied Catalysis A: General, 2014, vol. 472, p. 178 - 183
[2] Chemical Communications, 2012, vol. 48, # 76, p. 9468 - 9470
  • 9
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YieldReaction ConditionsOperation in experiment
87%
Stage #1: With hydrogen bromide; bromine In water at 0 - 20℃; for 0.166667 h;
Stage #2: With sodium nitrite In water at 0 - 5℃; for 0.5 h;
2-Amino-5-bromopyridine (2; 13.0 g, 75.1 mmol) was added over 10 min to a cold (10 °C) aq 47percent HBr (37 mL, 0.33 mol). Br2 (11 mL, 0.21mol) was added, keeping the temperature below 10 °C. Then, a solution of NaNO2 (16.1 g, 0.19 mol) in H2O (19 mL) was added dropwise, maintaining the temperature at 0–5 °C. The reaction mixture was stirred for an additional 30 min, then treated with a solution of NaOH (28.0 g, 0.70 mol) in H2O (30 mL) at such a rate that the temperature did not exceed 20–25 °C. The mixture was extracted with Et2O (3 × 40 mL) and the combined organic layers were dried (Na2SO4). The solvent was evaporated under vacuum, the residue was suspended in hexane (10 mL), and the solid formed was collected by filtration to afford a pale brown powder; yield: 15.49 g (87percent); mp 94–95 °C (Lit.19mp 96–97 °C); Rf = 0.55 (CHCl3). IR (KBr): 3411, 3022, 2924, 2852, 1549, 1437, 1356, 1090, 997 cm–1.1H NMR (CDCl3): δ = 7.39 (d, J = 8.4 Hz, 1 H, H-3), 7.67 (dd, J1 = 8.4 Hz,J2 = 2.5 Hz, 1 H, H-4), 8.45 (d, J = 2.4 Hz, 1 H, H-6). 13C NMR (CDCl3): δ = 120.1, 129.5, 140.4, 141.2, 151.3. MS (EI, 70 eV): m/z (percent) = 239 (36, [M (81Br, 81Br)]+), 237 (71, [M (79Br,81Br)]+), 235 (35, [M (79Br, 79Br)]+), 158 (85), 156 (85), 81 (57), 76 (78),50 (100).Anal. Calcd for C5H3Br2N: C, 25.35; H, 1.28; N, 5.91. Found: C, 25.46; H,1.13; N, 5.95.
83% With tert.-butylnitrite; trimethylbenzylammonium bromide In 1,2-dibromomethane at 20℃; [00159] Scheme 1. Preparation of relevant pyri(mi)dyl halides A-H. Key: (a) NBS, NH4OAc, MeCN, rt, 5 min, pyr: 85-90percent; pym: quant; (b) pyr: RCHO, Na(CN)BH3, MeCN, reflux, 1-12h (82percent, R = C5Hn); pym: NaH, Rl, THF, rt, overnight (85percent, R = Me); (c) Me3(Bn)NBr, f-BuONO, CH2Br2, rt, overnight, pyr: 77-83percent; pym: 30- 40percent; (d) pym: HI, CH2CI2, 0°C, 80-85percent; (e) i. NaOH, Br2, H20, rt, 50-60percent, ii. POCI3, PhNEt2, reflux, 4h, 75-85percent, iii. HI, CH2CI2, 0°C, 80-85percent; (f) ROH, Na, rt, 1-12 h, quant.; (g) RZnl, CI2Pd(PPh3)2, DMF/THF, rt, overnight, pyr (Br): 72percent (R = C6H13), pym (I) 81 percent, (R = C6H13); (h) alkyne, Cul, CI2Pd(PPh3)2, Et3N, MeCN, rt, 1-12 h, quant. [00160] Preparation of 3-pyridyl and 5-pyrimidyl halides. 2-Aminopyridine and 2-aminopyrimidine were employed as common starting materials for each of the pyridyl and pyrimidyl halides due to their commercial availability at very low cost. Synthesis of the various pyridyl bromides began with bromination of the 5-position of 2-aminopyridine using NBS/NH40AC (Das, B.; Venkateswarlu, K.; Majhi, A.; Siddaiah, V.; Reddy, K. R. J. Mol. Catal. A-Chem. 2007, 267, 30). This intermediate was either alkylated by reductive amination with appropriate aldehydes to prepare 5-bromo-2-N,N-dialkylaminopyridines (A) or subjected to aqueous (Bhasin, K. K.; Kumar, R.; Mehta, S. K.; Raghavaiah, P.; Jacob, C; Klapotke, T. M. Inorg. C im. Act. 2009, 362, 2386.) or non-aqueous (Nara, S. J.; Jha, M.; Brinkhorst, J.; Zemanek, T. J.; Pratt, D. A. J. Org. C em. 2008, 73, 9326.) diazotization/halo-dediazoniation to afford 2,5-dibromopyridine. This compound served as the precursor to all other substituted pyridines: 2-alkoxy-5-bromopyridines (C) were obtained by nucleophillic substitution with an appropriate sodium alkoxide17 and 2- alkynyl-5-bromopyridine (E) and 2-alkyl-5-bromopyridines (G) were prepared via Sonogoshira (Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386.) and Negeishi (Getmanenko, Y. A. ; Twieg, R. J. J. Org. Chem. 2008, 73, 830.) cross-coupling reactions, respectively.
58%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.166667 h;
Stage #2: With bromine In water at 0℃; for 0.25 h;
To a solution of 5-bromopyridin-2-amine (5.0 g, 28.9 mmol) in hydrogen bromide(50.0 mL, 46percent), sodium nitrite (15.0 g, 217.4 mmol) solution in water was slowlyadded at 0 °C. The resulting solution was stirred for 10 mm at the same temperature.Br2 (37.2 mL, 232.8 mmol) was slowly added to the reaction mixture at 0 °C andstirred for 15 mm at 0 °C. The reaction mixture was basified with sodium hydroxide and extracted with ethyl acetate, washed with sodium thiosulphate solution, water and brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuo. The product was purified by column chromatography toyield title compound (4.0 g, 58.0percent) white solid. LCMS: (M+H) = 237.9;1H NMR:(DMSO-d6, 300MHz) 6 8.57-8.58 (d, 1 H), 8.00- 8.04 (dd, 1 H), 7.64- 7.67(d, 1 H).
58%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.166667 h;
Stage #2: With bromine In water at 0℃; for 0.25 h;
To a solution of 5-bromopyridin-2-amine (5.0 g, 28.9 mmol) in hydrogen bromide (50.0 mL, 46percent), sodium nitrite (15.0 g, 217.4 mmol) solution in water was slowly added at 0 00 abd then stirred for 10 mm at the same temperature. To the reaction mixture Br2 (37.2 mL, 232.8 mmol) was slowly added at 0 00 and stirred for 15 mm at0 00. The reaction mixture was basified with sodium hydroxide and extracted with ethyl acetate, washed with sodium thiosulphate solution, water and brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuo. The product was purified by column chromatography to yield title compound (4.0 g, 58.0percent) white solid. LOMS: (M+H) = 237.9; 1H NMR: (DMSO-d6, 300MHz) 6 8.57-8.58 (d, 1 H), 8.00- 8.04 (dd, 1 H), 7.64- 7.67(d, 1 H).

Reference: [1] Synthesis (Germany), 2015, vol. 47, # 20, p. 3169 - 3178
[2] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
[3] Patent: WO2012/162818, 2012, A1, . Location in patent: Page/Page column 45-46
[4] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 107
[5] Patent: WO2014/202528, 2014, A1, . Location in patent: Page/Page column 102
[6] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[7] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
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Reference: [1] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[2] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
[3] Patent: WO2012/162818, 2012, A1,
[4] Patent: WO2014/202580, 2014, A1,
[5] Patent: WO2014/202528, 2014, A1,
[6] Synthesis (Germany), 2015, vol. 47, # 20, p. 3169 - 3178
  • 11
  • [ 96136-88-8 ]
  • [ 624-28-2 ]
  • [ 111110-50-0 ]
Reference: [1] Patent: US4877792, 1989, A,
  • 12
  • [ 109-04-6 ]
  • [ 624-28-2 ]
  • [ 75806-85-8 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 940,949
  • 13
  • [ 626-55-1 ]
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  • [ 2402-92-8 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 940,949
  • 14
  • [ 694-85-9 ]
  • [ 7789-69-7 ]
  • [ 624-28-2 ]
Reference: [1] Chemische Berichte, 1899, vol. 32, p. 1304
  • 15
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  • [ 73290-22-9 ]
Reference: [1] Inorganic Chemistry, 2010, vol. 49, # 12, p. 5625 - 5641
[2] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
[3] Tetrahedron, 2000, vol. 56, # 10, p. 1349 - 1360
[4] European Journal of Organic Chemistry, 2005, # 5, p. 822 - 837
[5] Tetrahedron, 2005, vol. 61, # 51, p. 12033 - 12041
[6] Angewandte Chemie - International Edition, 2001, vol. 40, # 4, p. 754 - 757
[7] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10480 - 10483
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  • [ 223463-13-6 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
  • 17
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  • [ 73290-22-9 ]
  • [ 116195-81-4 ]
  • [ 223463-13-6 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
  • 18
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  • [ 55717-45-8 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at 36℃; for 1.5 h; Inert atmosphere
Stage #2: With Trimethyl borate In tetrahydrofuran; diethyl ether at 2 - 6℃;
Stage #3: With dihydrogen peroxide; acetic acid In tetrahydrofuran; diethyl ether at 12℃; for 1.5 h; Cooling with ice
2,5-Dibromopyridine (V) (9.98 g, 42.1 mmol) was dissolved in 53 mL anhydrous (0032) THF under nitrogen in a 250 mL 3 -neck flask equipped with a mechanical stirrer, a thermocouple and a nitrogen inlet. A light tan solution was formed. A 2 M solution of i- PrMgCl in ether (23 mL) was added via syringe over 3 min. When approximately 50percent of the Grignard solution had been added, a brown suspension formed. Addition of z'-PrMgCl caused an exotherm to 36 °C. After stirring for 90 min, the suspension was cooled to 2 °C, and neat trimethylborate was added rapidly via syringe. The reaction exothermed to 6 °C, and the ice bath was removed. After stirring overnight, glacial acetic acid (3.79 g) was added, causing all solids to dissolve and a dark brown solution to form. The solution was cooled in an ice bath and 5.25 g of 30percent hydrogen peroxide (an oxidizing agent) was added dropwise at a rate which kept the reaction temperature from exceeding 12 °C. The reaction mixture was stirred for 90 min, and then diethyl ether (150 niL) and water (100 niL) were added . The aqueous layer was separated and extracted with ether (2 x 100 niL). The combined organics were washed with 100 mL 10percent sodium bisulfite solution and then brine. The extracts were dried (MgS04) and rotary evaporated to a brown oil which formed a tan solid on standing (7.95 g). The crude product was adsorbed onto 15 g Celite® and purified by flash chromatograph using a 220 g silica column and hexanes/EtOAc gradient. Fractions were evaporated to give 4.81 g (66percent yield) of an off-white solid. NMR spectra were identical to that of an authentic sample of 6-bromo-3-pyridinol. 1H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 7.94 (d, / = 3.0 Hz, 1H), 7.42 (d, / = 8.6 Hz, 1H), 7.17 (dd, = 3.0, 8.6 Hz, 1H); 13C NMR (DMSO-d6, 101 MHz) δ 153.74, 138.13, 129.30, 128.14, 126.21.
66%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at 36℃; for 1.55 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; diethyl ether at 2 - 6℃;
Stage #3: With dihydrogen peroxide; acetic acid In tetrahydrofuran; diethyl ether at 12℃; for 1.5 h;
2,5-Dibromopyridine (VII) (9.98 g, 42.1 mmol) was dissolved in 53 mL anhydrousTHF under nitrogen in a 250 mL 3-neck flask equipped with a mechanical stirrer, athermocouple and a nitrogen inlet. A light tan solution was formed. A 2 M solution of iPrMgC1 in ether (23 mL) was added via syringe over 3 mm. When approximately 50percent of theGrignard solution had been added, a brown suspension formed. Addition of the Mg reagent caused an exotherm to 36 °C. After stirring for 90 mm, the suspension was cooled to 2 °C, and neat trimethylborate (B(OMe)3) was added rapidly via syringe. The reaction exothermed to 6 °C, and the ice bath was removed. After stirring overnight, glacial acetic acid (3.79 g) was added, causing all solids to dissolve and a dark brown solution to form. The solution wascooled in an ice bath and 5.25 g of 30percent hydrogen peroxide (an oxidizing agent) was added dropwise at a rate which kept the reaction temperature from exceeding 12 °C. The reaction mixture was stirred for 90 mm, and then diethyl ether (150 mL) and water (100 mL) were added. The aqueous layer was separated and extracted with ether (2 x 100 mL). The combined organics were washed with 100 mL 10percent sodium bisulfite solution and then brine.The extracts were dried (MgSO4) and rotary evaporated to a brown oil which formed a tan solid on standing (7.95 g). The crude product was adsorbed onto 15 g Celite® and purified by flash chromatography using a 220 g silica column and hexanes/EtOAc gradient. Fractions were evaporated to give 4.81 g (66percent yield) of an off-white solid. NMR spectra were identical to that of an authentic sample of 6-bromo-3-pyridinol. ‘H NMR (DMSO-d6, 400 MHz) 10.24 (s, 1H), 7.94 (d, J = 3.0 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.17 (dd, J = 3.0, 8.6 Hz, 1H); ‘3C NMR (DMSO-d6, 101 MHz) 153.74, 138.13, 129.30, 128.14, 126.21.
66%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at 36℃; for 1.55 h; Inert atmosphere
Stage #2: With Trimethyl borate In tetrahydrofuran; diethyl ether at 6℃;
Stage #3: With dihydrogen peroxide; acetic acid In tetrahydrofuran; diethyl ether at 12℃; for 1.5 h;
2,5-Dibromopyridine (VI) (9.98 g, 42.1 mmol) was dissolved in 53 mL anhydrousTHF under nitrogen in a 250 mL 3-neck flask equipped with a mechanical stirrer, athermocouple and a nitrogen inlet. A light tan solution was formed. A 2 M solution of iPrMgC1 in ether (23 mL) was added via syringe over 3 mm. When approximately 50percent of theGrignard solution had been added, a brown suspension formed. Addition of i-PrMgC1 caused an exotherm to 36 °C. After stirring for 90 mm, the suspension was cooled to 2 °C, and neat trimethylborate (B(OMe)3) was added rapidly via syringe. The reaction exothermed to 6 °C, and the ice bath was removed. After stirring overnight, glacial acetic acid (3.79 g) was added, causing all solids to dissolve and a dark brown solution to form. The solution was cooled inan ice bath and 5.25 g of 30percent hydrogen peroxide (an oxidizing agent) was added dropwise at a rate which kept the reaction temperature from exceeding 12 °C. The reaction mixture was stirred for 90 mm, and then diethyl ether (150 mL) and water (100 mL) were added . The aqueous layer was separated and extracted with ether (2 x 100 mL). The combined organics were washed with a 100 mL 10percent sodium bisulfite solution and then brine. The extracts weredried (MgSO4) and rotary evaporated to a brown oil which formed a tan solid on standing (7.95 g). The crude product was adsorbed onto 15 g Celite® and purified by flash chromatography using a 220 g silica column and hexanes/EtOAc gradient. Fractions were evaporated to give 4.81 g (66percent yield) of an off-white solid. NMR spectra were identical to that of an authentic sample of 6-bromo-3-pyridinol. ‘H NMR (DMSO-d6, 400 mHz) 10.24(s, 1H), 7.94 (d, J= 3.0 Hz, 1H), 7.42 (d, J= 8.6 Hz, 1H), 7.17 (dd, J= 3.0, 8.6 Hz, 1H); ‘3C NMR (DMSO-d6, 101 MHz) 153.74, 138.13, 129.30, 128.14, 126.21.
Reference: [1] Patent: WO2017/87597, 2017, A1, . Location in patent: Page/Page column 4; 5
[2] Patent: WO2017/87619, 2017, A1, . Location in patent: Page/Page column 5; 6
[3] Patent: WO2017/87643, 2017, A1, . Location in patent: Page/Page column 5; 6
[4] ChemPlusChem, 2017, vol. 82, # 5, p. 758 - 769
[5] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 23, p. 5835 - 5839
[6] Patent: EP1935890, 2008, A1, . Location in patent: Page/Page column 48; 49
[7] Patent: EP1905769, 2008, A1, . Location in patent: Page/Page column 58
[8] Organic Letters, 2011, vol. 13, # 12, p. 3008 - 3011
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YieldReaction ConditionsOperation in experiment
57% With n-butyllithium; acetic acid In tetrahydrofuran; hexane; N,N-dimethyl-formamide; toluene WORKING EXAMPLE 6
Production of 5-bromo-3-formylpyridine
n-Butylmagnesium chloride (4.00 mmol) in 2.00M tetrahydrofuran solution (2.00 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.55M hexane (5.20 mL).
The mixture was stirred at 0° C. for 15 minutes to give a suspension.
The suspension was added to a mixture of toluene (15 mL) and tetrahydrofuran (10 mL) containing 2,5-dibromo-pyridine (2.37 g, 10.0 mmol) over a period of 10 minutes or more while keeping the temperature below 5° C. to give an orange solution.
The solution was stirred at 0° C. for one hour, and N,N-dimethylformamide (1.0 mL, 13 mmol)was added thereto.
The resultant suspension was stirred at room temperature for 30 minutes, and tetrahydrofuran (10 mL) was added, followed by further stirring at room temperature for 30 minutes.
After addition of 1M aqueous acetic acid (20 mL) to the suspension, the organic phase was separated, and the aqueous phase was extracted with toluene(20 mL).
The organic phase and the toluene extract were combined, washed with an aqueous sodium chloride saturated solution (15 mL), dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent.
The resultant residue was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (10:1, v/v) to give the title compound (1.062 g, 57percent yield) as a colorless solid. 1H-NMR(CDCl3) δppm:8.31 (1H, dd, J=1.5, 2.2 Hz), 8.92 (1H, d, J=2.2 Hz), 9.00 (1H, d, J=1.5 Hz), 10.09 (1H, s).
Reference: [1] Patent: US2003/130511, 2003, A1,
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  • [ 81971-39-3 ]
Reference: [1] Patent: WO2013/49565, 2013, A1,
[2] Patent: WO2013/49559, 2013, A1,
[3] Synlett, 2015, vol. 26, # 11, p. 1557 - 1562
  • 21
  • [ 624-28-2 ]
  • [ 2859-68-9 ]
Reference: [1] Journal of Organic Chemistry, 1988, vol. 53, # 2, p. 386 - 390
  • 22
  • [ 624-28-2 ]
  • [ 51834-97-0 ]
Reference: [1] Patent: US2012/46290, 2012, A1,
[2] Patent: EP1047418, 2005, B1,
  • 23
  • [ 624-28-2 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
95% With sodium methylate In methanol; water Step 1.
5-Bromo-2-methoxypyridine

A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 rmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) Rf0.57.
95% With sodium methylate In methanol; water Step 1.
5-Bromo-2-methoxypyridine
A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70 ° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mmL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc /90percent hexane) R.f.0.57.
95% With sodium methylate In methanol at 70℃; for 42 h; A13k. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction ; [] Step 1. 5-Bromo-2-methoxypyridine: A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95percent yield): TLC (10percent EtOAc / 90percent hexane) Rf 0.57.
83% With ammonium chloride; sodium In methanol Reference Example 10
5-Bromo-2-methoxypyridine
After sodium (10 g, 0.435 mol) was dissolved in methanol (500 ml), 2,5-dibromopyridine (50 g, 0.211 mol) was added thereto and the mixture was heated for 2 days under reflux.
The reaction solution was cooled as it was, and then concentrated.
Then, the residue was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride.
The organic layer was washed with an aqueous saturated solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated, to give the title compound (33 g, 83percent) as a pale brown oil.
1H NMR (400 MHz, DMSO-d6) δ ppm; 3. 84 (3H, s), 6. 72(1H, dd, J= 0. 8, 8. Hz), 7. 89 (1H, dd, J= 2. 4, 8. 8 Hz), 8. 29 (1H, dd, J= 0. 8, 2.4 Hz).
83%
Stage #2: for 48 h; Heating / reflux
Reference Example 10
5-Bromo-2-methoxypyridine
After sodium (10 g, 0.435 mol) was dissolved in methanol (500 ml), 2,5-dibromopyridine (50 g, 0.211 mol) was added thereto and the mixture was heated for 2 days under reflux.
The reaction solution was cooled as it was, and then concentrated.
Then, the residue was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride.
The organic layer was washed with an aqueous saturated solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated, to give the title compound (33 g, 83percent) as a pale brown oil.
1H NMR (400 MHz, DMSO-d6) δ ppm; 3.84 (3H, s), 6.72 (1H, dd, J=0.8, 8.8 Hz), 7.89 (1H, dd, J=2.4, 8.8 Hz), 8.29 (1H, dd, J=0.8, 2.4 Hz).

Reference: [1] Patent: US2002/65296, 2002, A1,
[2] Patent: US2004/102636, 2004, A1,
[3] Patent: EP1042305, 2005, B1, . Location in patent: Page/Page column 32-33
[4] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
[5] Patent: EP1308441, 2003, A1,
[6] Patent: US2004/6082, 2004, A1, . Location in patent: Page/Page column 23
[7] Patent: US5512575, 1996, A,
[8] Patent: US2002/137770, 2002, A1,
[9] Patent: US5922742, 1999, A,
[10] Patent: US5714496, 1998, A,
  • 24
  • [ 624-28-2 ]
  • [ 124-41-4 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
95% at 70℃; for 42 h; A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95percent yield): TLC (10percent EtOAc / 90percent hexane) Rf 0.57
95% at 70℃; for 42 h; B3k. General Method for Substituted Aniline Formation Via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction; Step 1. 5-Bromo-2-methoxypyridine; A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2.x.100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) Rf 0.57.
95% at 70℃; for 42 h; Step 1.
5-Bromo-2-methoxypyridine

A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) Rf 0.57.
95% at 70℃; for 42 h; Sealed tube Step 1.
5-Bromo-2-methoxypyridine
A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) Rf 0.57.
95% at 70℃; for 42 h; A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95percent yield): TLC (10percent EtOAc / 90percent hexane) Rf 0.57.
78.6% for 17 h; Heating / reflux 1)
5-Bromo-2-methoxypyridine
Sodium methoxide (55.2 g) was added to 2,5-dibromopyridine (50.0 g) in methanol (100 mL).
The resultant mixture was refluxed for 17 hours, followed by cooling in air.
The formed salt was separated by filtration, and the filtrate solvent was evaporated under reduced pressure.
5percent Aqueous sodium hydrogencarbonate and diethyl ether were added thereto for partitioning the residue.
The organic layer was washed with saturated brine, followed by drying over magnesium sulfate anhydrate.
After a filtration step, the solvent was evaporated under reduced pressure, to thereby give 5-bromo-2-methoxypyridine as an oily product (31.2 g, 78.6percent).
1H-NMR (300MHz, CDCl3) δ:3.91 (3H, s), 6.66 (1H, d, J=8.81Hz), 7.63 (1H, dd, J=8.81, 2.39Hz), 8.20 (1H, d, J=2.39Hz).
58% at 20 - 70℃; for 1 h; Step 1: 5-Bro -2-methoxypyridine A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70°C for 1 hour and then allowed to cool to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give a pale yellow volatile oil (2.5 g, 58percent yield). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.87 (dd, 1H), 6.81 (d, 1H), 3.82 (s, 3H).

Reference: [1] Patent: EP1449834, 2004, A2, . Location in patent: Page 27
[2] Patent: US2007/244120, 2007, A1, . Location in patent: Page/Page column 20
[3] Patent: US2003/207914, 2003, A1, . Location in patent: Page/Page column 12
[4] Patent: US2012/46290, 2012, A1, . Location in patent: Page/Page column 20
[5] Patent: EP1047418, 2005, B1, . Location in patent: Page/Page column 33
[6] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[7] Bulletin des Societes Chimiques Belges, 1986, vol. 95, # 11, p. 1009 - 1020
[8] Journal of Medicinal Chemistry, 2000, vol. 43, # 11, p. 2217 - 2226
[9] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1583 - 1592
[10] Journal of the American Chemical Society, 1997, vol. 119, # 33, p. 7694 - 7701
[11] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 26-27
[12] Patent: WO2013/49559, 2013, A1, . Location in patent: Page/Page column 67
[13] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 8, p. 1077 - 1080
[14] Patent: WO2013/49565, 2013, A1, . Location in patent: Page/Page column 72
  • 25
  • [ 624-28-2 ]
  • [ 67-56-1 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
98% for 5 h; Reflux (1) In a 500 ml reaction flask, 47 g of 2,5-dibromopyridine,8 g of solid sodium hydroxide and 200 ml of methanol,Stirring began to heat up to reflux, the reaction time was 5 hours,Stop the reaction, steamed most of the methanol, cooled, add 100 ml of water,Extract once with dichloromethane, remove methylene chloride to give the crude product,The crude product was distilled under reduced pressure to give 2-methoxy-5-bromopyridine,The yield is 98percent.
Reference: [1] Patent: CN106905229, 2017, A, . Location in patent: Paragraph 0026; 0027
[2] Journal of Organic Chemistry, 1999, vol. 64, # 3, p. 836 - 842
[3] Patent: US2004/102472, 2004, A1, . Location in patent: Page 37
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 26
  • [ 624-28-2 ]
  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
95% at 70℃; for 42 h; Step 1.
5-Bromo-2-methoxypyridine
A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) 190.57.
Reference: [1] Patent: US2008/269265, 2008, A1, . Location in patent: Page/Page column 17
[2] Synthesis, 2012, vol. 44, # 1, p. 57 - 62
  • 27
  • [ 624-28-2 ]
  • [ 13472-85-0 ]
Reference: [1] Patent: US2003/96829, 2003, A1,
  • 28
  • [ 624-28-2 ]
  • [ 74-89-5 ]
  • [ 84539-30-0 ]
YieldReaction ConditionsOperation in experiment
100% at 80℃; for 24 h; 2,5-Dibromopyridinc (2.5 g, 10.6 mmol) was treated with a 33percent MeNH2ZEtOH (13.2 ml, 106 mmol) at 800C for several days. The solvent was evaporated, the residue was dissolved in 1 M HCl and the aqueous solution was washed with DCM. The acidic layer was basified with 1 M NaOH to pH ~1 1 and the milky suspension was extracted with DCM. The organic layer was dried over MgSO.* and evaporated to give the target product as a brown solid in quantitative yield. (Calculated mass: 187.0, observed mass: 188.3).
1.20 g at 80℃; for 72 h; Synthesis of (5-bromo-pyridin-2-yl)-methyl-amine
A 20 ml microwave reaction vessel is charged with 2,5-Dibromo-pyridine (2.00 g, 8.44 mmol) and treated with methylamine (10.45 ml of a 33percent solution in ethanol, 84.43 mmol) and warmed to 80° C. for 3 days.
After this time the reaction is concentrated and the remaining solid is treated with 1M HCl (50 ml) and DCM.
The layers are separated and the aqueous phase is basified using 1N NaOH (to pH˜11).
The product was extracted into DCM (2*) and the combined organics were dried (MgSO4), filtered and concentrated to give the desired product I-96bis (1.20 g).
1H-NMR (400 MHz, DMSO-d6): 2.75 ppm (d, 3H), 6.44 ppm (d, 1H), 6.72 ppm (bs, 1H), 7.51 ppm (dd, 1H), 8.05 ppm (s, 1H)
Reference: [1] Patent: WO2008/89034, 2008, A2, . Location in patent: Page/Page column 127
[2] Patent: US2013/195879, 2013, A1, . Location in patent: Paragraph 0292; 0293
[3] Patent: CN104292242, 2017, B, . Location in patent: Paragraph 0105; 0111; 0112; 0113
  • 29
  • [ 624-28-2 ]
  • [ 84539-30-0 ]
Reference: [1] Patent: US2011/117055, 2011, A1,
  • 30
  • [ 624-28-2 ]
  • [ 50720-12-2 ]
Reference: [1] Patent: US2003/65018, 2003, A1,
  • 31
  • [ 624-28-2 ]
  • [ 124-38-9 ]
  • [ 30766-11-1 ]
YieldReaction ConditionsOperation in experiment
47%
Stage #1: With n-butyllithium In toluene at -78℃; for 2 h;
Stage #2: at -78℃; for 1 h;
Stage #3: With hydrogenchloride In water; toluene
Toluene (114 mL) was cooled to -78 °C, n-BuLi (79.7 mL, 127 mmol) was added dropwise at the same temperature followed by 2,5-dibromopyridine (30 g, 120 mmol) in toluene (60 mL) and stirred for 2 h. The Reaction mixture was bubbled with dry carbon dioxide gas for 1 h at -78 °C. Progress of the reaction was monitored by TLC. On completion of the reaction, reaction contents were warmed to room temperature and toluene was distilled under reduced pressure. Then water (200 mL) was added to the reaction mixture and filtered on celite bed. The filtrate was acidified with diluted HCI solution, solid was precipitated out which was filtered and dried over sodium sulphate to yield 5-bromopicolinic acid (12 g, 47 percent yield) as a brown colored solid.
47%
Stage #1: With n-butyllithium In toluene at -78℃; for 2 h;
Stage #2: at -78℃; for 1 h;
Step 1
Toluene (114 mL) was cooled to 78° C., n-BuLi (79.7 mL, 127 mmol) was added dropwise at the same temperature followed by 2,5-dibromopyridine (30 g, 120 mmol) in toluene (60 mL) and stirred for 2 h.
The Reaction mixture was bubbled with dry carbon dioxide gas for 1 h at 78° C.
Progress of the reaction was monitored by TLC.
On completion of the reaction, reaction contents were warmed to room temperature and toluene was distilled under reduced pressure.
Then water (200 mL) was added to the reaction mixture and filtered on celite bed.
The filtrate was acidified with diluted HCl solution, solid was precipitated out which was filtered and dried over sodium sulfate to yield 5-bromopicolinic acid (12 g, 47percent yield) as a brown colored solid.
Reference: [1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[2] Patent: WO2013/13815, 2013, A1, . Location in patent: Page/Page column 149; 150
[3] Patent: US2013/29962, 2013, A1, . Location in patent: Paragraph 0824
[4] Tetrahedron, 2005, vol. 61, # 45, p. 10748 - 10756
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1407 - 1412
[6] Patent: WO2009/55828, 2009, A1, . Location in patent: Page/Page column 282
  • 32
  • [ 624-28-2 ]
  • [ 30766-11-1 ]
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
[2] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
  • 33
  • [ 624-28-2 ]
  • [ 64-17-5 ]
  • [ 55849-30-4 ]
YieldReaction ConditionsOperation in experiment
95% With sodium In N,N-dimethyl-formamide at 80℃; for 1 h; Freshly cut sodium (74 mg, 3.2 mmol) was dissolved in ethanol (1.2 ml) followed by addition of 2,5-dibromopyridine (236 mg, lmmol) in DMF (3 ml). The mixture was stirred for Ih at 8O0C, and cooled to rt. The reaction was quenched with water (4 mL) and extracted with ether three times. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography to afford the target product as a white solid (192 mg, 95percent). MS (m/z) (M~+H): 202, 204.
Reference: [1] Patent: WO2009/155527, 2009, A2, . Location in patent: Page/Page column 127
[2] Recueil des Travaux Chimiques des Pays-Bas, 1949, vol. 68, p. 275,282
  • 34
  • [ 624-28-2 ]
  • [ 141-52-6 ]
  • [ 55849-30-4 ]
YieldReaction ConditionsOperation in experiment
88% for 18 h; Heating / reflux A solution of freshly prepared sodium ethoxide (sodium, 4.9 g, 210 mmol; absolute ethanol, 100 mL, room temperature) was treated with 2,5-dibromopyridine (10 g, 42 mmol) and was heated at reflux for 18 h. After cooling to room temperature, the mixture was poured into aqueous saturated sodium bicarbonate solution, was extracted with diethyl ether, and the ether layer was washed with brine, was dried over magnesium sulfate, was concentrated in vacuo. Purification by silica gel chromatography (100:1 hexanes-ethyl acetate) gave 7.5 g (88percent yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 162.9, 147.7, 141.2, 112.9, 111.6, 62.3, 14.7; MS (AP/CI) 202.1, 204.1 (M+H)+.
88% for 18 h; Heating / reflux A solution of freshly prepared sodium ethoxide (sodium, 4.9g, 210 mmol; absolute ethanol, 100 mL, room temperature) was treated with 2,5-dibromopyridine (10g, 42 mmol) and was heated at reflux for 18 hours. After cooling to room temperature, the mixture was poured into aqueous saturated sodium bicarbonate solution, was extracted with diethyl ether, and the ether layer was washed with brine, was dried over magnesium sulfate, was concentrated in vacuo. Purification by silica gel chromatography (100:1 hexanes-ethyl acetate) gave 7.5 g (88percent yield) of the title compound. 13C NMR (100 MHz, CDCI3) d 162.9,147.7, 141.2, 112.9, 111.6, 62.3, 14.7; MS (AP/CI) 202.1 , 204.1 (M+H)+.
Reference: [1] Patent: US2006/25421, 2006, A1, . Location in patent: Page/Page column 15
[2] Patent: WO2006/106416, 2006, A1, . Location in patent: Page/Page column 36
  • 35
  • [ 624-28-2 ]
  • [ 55849-30-4 ]
Reference: [1] Patent: US2002/37889, 2002, A1,
  • 36
  • [ 624-28-2 ]
  • [ 68-12-2 ]
  • [ 26163-07-5 ]
YieldReaction ConditionsOperation in experiment
82% With sodium t-butanolate In water at 140℃; for 6 h; Sealed tube 2,5-dibromopyridine (1.0 mmol), DMF (1 mmol),Sodium tert-butoxide (0.5-4.0 mmol) and 2 mL of water were successively added to a 10 mL sealed tube, and the mixture was heated and stirred for 6 hours in an oil bath at 140 ° C, and quenched with dichloromethane.When the reaction is over,The yield of the product can be determined by GC and GC-MS by adding the internal standard to the crude product.When the sodium tert-butoxide was 0.5 mmol, 1.0 mmol, 2.0 mmol, 3.0 mmol, and 4.0 mmol, the isolated yields of the products were 55percent, 66percent, 72percent, 80percent, and 82percent, respectively.
Reference: [1] Patent: CN108689923, 2018, A, . Location in patent: Paragraph 0016-0029
  • 37
  • [ 624-28-2 ]
  • [ 26163-07-5 ]
YieldReaction ConditionsOperation in experiment
86% With dimethyl amine In tetrahydrofuran A.
5-Bromo-2-(dimethylamino)pyridine
A solution of 2,5-dibromopyridine (11.84 g, 50.0 mmol) in 2.0 M solution of dimethylamine in tetrahydrofuran (100 mL) in a sealed tube was heated at 120° C. for 12 hours.
The reaction was quenched with ethyl acetate and washed with water.
The organic layer was dried over magnesium sulfate, filtered, and concentrated.
The residue was then purified by chromatography (SiO2, 10-15percent ethyl acetate/hexane) to provide the title compound (8.67 g, 86percent yield): 1H NMR (CDCl3) 8.16 (d, 1H), 7.49 (dd, 1H), 6.41 (d, 1H), 3.05 (s, 6H); ES-MS m/z 201 [M+H]+.
Reference: [1] Patent: US6593322, 2003, B1,
  • 38
  • [ 624-28-2 ]
  • [ 124-40-3 ]
  • [ 26163-07-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[2] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 4, p. 374 - 378
[3] Patent: WO2012/167423, 2012, A1, . Location in patent: Page/Page column 36
[4] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0168; 0169
  • 39
  • [ 624-28-2 ]
  • [ 15862-19-8 ]
YieldReaction ConditionsOperation in experiment
70% With bis-triphenylphosphine-palladium(II) chloride In tetrahydrofuran at 20℃; for 0.5 h; Inert atmosphere General procedure: Into a 25 mL round bottomed flask were added Pd(PPh3)2Cl2 (0.12 g, 2.0 mol percent), 2,5-dibromopyridine (1.18 g, 5.0 mmol) and 10.0 mL of 2-(ethoxycarbonyl)phenylzinc bromide (0.5 M in THF, 5.0 mmol) under an argon atmosphere at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. Quenched with saturated NH4Cl solution, then extracted with ethyl ether (10 mL × 3). Washed with saturated NaHCO3, Na2S2O3 solution and brine, then dried over anhydrous MgSO4. Purification by column chromatography on silica gel (10percent ethyl acetate/90percent heptane) afforded 1.02 g of 1a in 67percent isolated yield as a colorless oil.
63% With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 0 - 20℃; for 5 h; Inert atmosphere Example 1
<Synthesis of 2,7-bis(2,2'-bipyridin-5-yl)triphenylene (compound 3)>
2,5-Dibromopyridine (19.5 g), 2-pyridylzinc bromide (150 ml), tetrahydrofuran (90 ml), and tetrakis(triphenylphosphine)palladium(0) (4.33 g) were added to a nitrogen-substituted reaction vessel.
After being cooled, the mixture was stirred at 0°C for 2 hours, and then at room temperature for 3 hours.
The reaction mixture was added to a 10percent disodium dihydrogen ethylenediamine tetraacetate aqueous solution, and stirred for 6 hours.
The organic layer was collected by separation after adding chloroform (300 ml) .
The organic layer was dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product.
The crude product was purified by column chromatography (support: silica gel, eluent: toluene) to obtain a white powder of 5-bromo-2,2'-bipyridine (11.1 g; yield 63percent).
63% With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 0 - 20℃; for 5 h; Inert atmosphere Example 1
<Synthesis of 3,3'-bis(2,2'-bipyridin-5-yl)-1,1':2',1'-terphenyl (compound 2)>
2,5-Dibromopyridine (19.5 g), 2-pyridylzinc bromide (150 ml), tetrahydrofuran (90 ml), and tetrakis(triphenylphosphine)palladium(0) (4.33 g) were added to a nitrogen-substituted reaction vessel.
After being cooled, the mixture was stirred at 0°C for 2 hours, and then at room temperature for 3 hours.
The reaction mixture was added to a 10percent disodium dihydrogen ethylenediamine tetraacetate aqueous solution, and stirred for 6 hours.
The organic layer was collected by separation after adding chloroform (300 ml) .
The organic layer was dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product.
The crude product was purified by column chromatography (support: silica gel, eluent: toluene) to obtain a white powder of 5-bromo-2,2'-bipyridine (11.1 g; yield 63percent).
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 22, p. 5330 - 5337
[2] Dalton Transactions, 2015, vol. 44, # 22, p. 10423 - 10430
[3] Inorganic Chemistry, 2018, vol. 57, # 7, p. 3602 - 3614
[4] Synlett, 2003, # 6, p. 852 - 854
[5] Chemical Communications, 2015, vol. 51, # 38, p. 8161 - 8164
[6] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 1, p. 280 - 282
[7] Patent: EP2679581, 2014, A1, . Location in patent: Paragraph 0127
[8] Patent: EP2679582, 2014, A1, . Location in patent: Paragraph 0099
[9] Inorganic Chemistry, 2010, vol. 49, # 21, p. 10183 - 10190
[10] Canadian Journal of Chemistry, 2009, vol. 87, # 4, p. 533 - 538
  • 40
  • [ 624-28-2 ]
  • [ 13737-05-8 ]
  • [ 15862-19-8 ]
YieldReaction ConditionsOperation in experiment
63% With tetrakis(triphenylphosphine) palladium(0) In 5,5-dimethyl-1,3-cyclohexadiene for 15 h; Reflux 1.91 g (7.89 mmol, 1.0 eq) 2-(trimethylstannyl)pyridine and 2.08 g (8.77 mmol, 1.1 eq), 2,5-dibromopyridine are dissolved in 16 mL freshly distilled xylene. The degassed solution is treated with0.061 g (0.053 mmol, 0.06 eq) Pd(PPh3)4 and stirred under reflux for 15 hours. After addition of 40 mL2N NaOH, the mixture is extracted with 40 mL toluene (3x). The organic phase is washed with brine,dried over MgSO4 and the solvent is removed in vacuo. Purification via column chromatography (SiO2,3.5 x 10 cm, pentane/EtOAc = 20/1 10/1) yields 2.57 g (63percent) 5-bromo-2,2’-bipyridine as colourlesssolid.
Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 443 - 449
[2] Synlett, 2016, vol. 27, # 7, p. 1056 - 1060
[3] Inorganica Chimica Acta, 2013, vol. 395, p. 145 - 150
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1670 - 1673
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  • [ 17997-47-6 ]
  • [ 15862-19-8 ]
Reference: [1] Inorganic Chemistry, 2015, vol. 54, # 4, p. 1414 - 1425
[2] Chemical Communications, 2016, vol. 52, # 18, p. 3713 - 3716
[3] Tetrahedron Letters, 2001, vol. 42, # 18, p. 3203 - 3206
[4] Dalton Transactions, 2013, vol. 42, # 6, p. 2062 - 2074
[5] Dalton Transactions, 2013, vol. 42, # 18, p. 6478 - 6488
[6] Inorganic Chemistry Communications, 2016, vol. 64, p. 13 - 15
[7] Science China Chemistry, 2016, vol. 59, # 1, p. 70 - 77
[8] ACS Chemical Neuroscience, 2017, vol. 8, # 4, p. 723 - 730
[9] Journal of the American Chemical Society, 2017, vol. 139, # 23, p. 7745 - 7748
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  • [ 15862-19-8 ]
Reference: [1] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2010, vol. 65, # 3, p. 329 - 336
[2] Dalton Transactions, 2011, vol. 40, # 45, p. 12060 - 12062
[3] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1911 - 1923
[4] Journal of Organic Chemistry, 2007, vol. 72, # 18, p. 6653 - 6661
  • 43
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  • [ 624-28-2 ]
  • [ 1461-22-9 ]
  • [ 15862-19-8 ]
Reference: [1] Tetrahedron Letters, 2003, vol. 44, # 42, p. 7711 - 7714
  • 44
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  • [ 15862-18-7 ]
YieldReaction ConditionsOperation in experiment
80% With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane In benzene for 72 h; Heating To the 250 ml 2-neck flask was added 2,5-Dibromopyridine (8 g, 33.8 mmol), hexamethylditin (5.53 g, 0.0169 mmol) and Pd (PPh3) 4 (0.80 g)And the mixture was heated with stirring for 72 hours.After completion of the reaction, the temperature was lowered to room temperature,After the excess ether was added, the resulting solid product was filtered and subjected to column chromatography using chloroform and methanol to obtain 4.21 g (yield: 80percent) of Compound A
80% With tetrakis(triphenylphosphine) palladium(0); bis(tri-n-butyltin) In m-xylene at 130℃; for 72 h; Darkness With m-xylene as the solvent, 2,5-dibromopyridine (5.0 mmol) was addedReacts with n-butyltin (5.5 mmol),Using tetrakis(triphenylphosphine)palladium as a catalyst, the reaction was carried out at 130°C in the dark for three days. After the reaction, ethylenediaminetetraacetic acid disodium salt was added to remove the remaining tin reagent. The organic phase was collected by extracting the mixture with dichloromethane and concentrating. The crude product was isolated by column chromatography to give the pure product. Yield: 80percent.
42%
Stage #1: With bis(tri-n-butyltin) In xylene at 60℃; for 0.25 h;
Stage #2: at 120℃; for 8 h;
A reaction vessel was charged with 6.0 g of 2,5-dibromopyridine, 7.0 ml of bistributyltin, and 120 ml of xylene, followed by heating and stirring at 60°C for 15 minutes. Further, 700 mg of tetrakis(triphenylphosphine)palladium was added thereto, followed by stirring at 120°C for 8 hours. After cooling to room temperature, the insoluble materials were removed by filtration, and the filtrate was washed with 150 ml of an aqueous ethylenediamine tetraacetate solution. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: silica gel, eluent: cyclohexane/toluene) to obtain 1.7 g (yield 42percent) of 5,5'-dibromo-[2,2']bipyridine as a yellow powder.
Reference: [1] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 10, p. 1226 - 1231
[2] Patent: KR2017/79357, 2017, A, . Location in patent: Paragraph 0231-0234
[3] Patent: CN104086596, 2017, B, . Location in patent: Paragraph 0035; 0036
[4] Synthesis, 2005, # 3, p. 458 - 464
[5] Chemistry - A European Journal, 2006, vol. 12, # 16, p. 4351 - 4361
[6] Patent: EP2241568, 2010, A1, . Location in patent: Page/Page column 43
[7] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[8] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 443 - 449
[9] European Journal of Inorganic Chemistry, 2009, # 32, p. 4850 - 4859
[10] Patent: WO2018/127540, 2018, A1,
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  • [ 96-22-0 ]
  • [ 626-55-1 ]
  • [ 874915-22-7 ]
  • [ 15862-18-7 ]
  • [ 874915-24-9 ]
  • [ 19780-41-7 ]
YieldReaction ConditionsOperation in experiment
33% With n-butyllithium In toluene at 0℃; for 0.0833333 h; EXAMPLE 1 2-(3-hydroxy-pentane-3-yl)-5-bromo-pyridine(Batch Process) A toluene solution (24 mL) containing 2,5-dibromopyridine (21.11 mmoles) ad 3-pentanone (21.11 mmoles) were placed in a 125 mL jacketed flask under N2 at 20 C. in an ice bath. n-BuLi in hexanes (17.2 mL, 1.3 M, 22.36 moles; 1.06 equiv) was added via a syringe pump delivering at 0.25 mL/min. The mixture was stirred for 5 min and then quenched with 30 mL of MeOH. The reaction mixture was diluted with EtOAc (10 ?L in 1 mL EtOAc) and analyzed by GC/MS. The major product was 2-(3-hydroxy-pentane-3-yl)-5-bromo-pyridine (55.33percent) indicating selective lithiation at the 2 position. The major product was isolated and purified by column chromatography to afford 33percent isolated yield.
Reference: [1] Patent: US2006/30714, 2006, A1, . Location in patent: Page/Page column 6
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  • [ 400859-07-6 ]
Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 443 - 449
  • 47
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  • [ 223463-10-3 ]
Reference: [1] Chemistry - A European Journal, 1999, vol. 5, # 3, p. 854 - 859
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  • [ 223463-10-3 ]
Reference: [1] Chemistry - A European Journal, 1999, vol. 5, # 3, p. 854 - 859
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  • [ 15862-18-7 ]
Reference: [1] Polish Journal of Chemistry, 2009, vol. 83, # 2, p. 245 - 262
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  • [ 75754-04-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
  • 51
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  • [ 100-51-6 ]
  • [ 83664-33-9 ]
YieldReaction ConditionsOperation in experiment
92% With potassium hydroxide In toluene for 1.5 h; Heating / reflux A mixture of 2,5-dibromopyridine (20 g, 84.4 MMOL), DIBENZO-18-CROWN-6 (1.5 g, 4. 2mmol), benzyl alcohol (11. 9 g, 11.4 mL, 109.8 mmol), potassium hydroxyde (11. 4 g, 202.6 mmol) and toluene (200 mL) was atirred at reflux with a Dean-Stark apparatus for 1.5 hours. After removal of solvent in reduced pressure, the residue was diluted with water, and extracted with chloroform. The separated organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (hexane: ethyl acetate, 98: 2) followed by recrystallization from hexane, to give 2- (BENZYLOXY)-5- bromopyridine (20.6 g, 92percent) as a colorless solid.
92% With potassium hydroxide In toluene for 1.5 h; Heating / reflux under azeotropic conditions A mixture of 2,5-dibromopyridine (20.0 g, 84.4 mmol), dibenzo-18-crown-6 (1.5 g, 4.2 mmol), benzyl alcohol (11.9 g, 11.4 mL, 109.8 mmol) and KOH (11.4 g, 202.6 mmol) in toluene (200 mL) was refluxed with Dean-Stark for 1.5 hours. After removal of solvent under reduced pressure, the residue was diluted with water, and extracted with chloroform. The separated organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica-gel, (hexane:ethyl acetate, 98:2) followed by recrystallization from hexane, to give 2-benzyloxy-5-bromopyridine (20.6 g, 92 percent) as a colorless solid.
90%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 1 h;
Manufacturing Example 12-1-1 2-Benzyloxy-5-bromopyridine; To a solution of phenyl-methanol (20.5 g, 190 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2,5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into is water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90percent).1H-NMR Spectrum (CDCl3) δ (ppm): 5.34 (2H, s), 6.71-6.73 (1H, m), 7.32-7.45 (5H, m), 7.64-7.67 (1H, m), 8.20-8.21 (1H, m).
90%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 1 h;
To a solution of phenyl-methanol (20.5 g, 190 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2,5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 5.34 (2H, s), 6.71-6.73 (1H, m), 7.32-7.45 (5H, m), 7.64-7.67 (1H, m), 8.20-8.21 (1H, m).
85% With potassium hydroxide In toluene for 3 h; Heating / reflux A suspension of 2, 5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, . 05 equiv), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium hydroxide [(1. 1] g, 2.4 equiv) in toluene (30 mL) were heated at reflux for 3 h in an apparatus fitted with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in water, and extracted into methylene chloride. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85percent) which was used without purification. Mass spec.: 264.25 (MH) [+.]
71.2%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 20℃;
To a solution of sodium hydride (1.04 g, 26.0 mmol, 1.3 equiv)In N, N-dimethylformamide (30 ml) was added benzyl alcohol (2.59 g, 24.0 mmol, 1.2 equiv)The mixture was stirred at 0 ° C for 1 hour,Followed by the addition of 2,5-dibromopyridine (4.74 g, 20 mmol, 1.0 equiv)The reaction solution was allowed to react overnight at room temperature.The reaction was diluted with ethyl acetate (300 mL), washed with half-saturated brine (300 mL x 4) and the organic phase was dried over anhydrous sodium sulfate. The filtrate was chromatographed three times with petroleum ether and the residue was purified by column chromatography (Eluent: petroleum ether: ethyl acetate = 200: 1) to give 2- (benzyloxy) -5-bromopyridine (3.76 g, yield: 71.2percent).

Reference: [1] Journal of Organic Chemistry, 1995, vol. 60, # 5, p. 1408 - 1412
[2] Polyhedron, 2013, vol. 52, p. 755 - 760
[3] Patent: WO2004/43926, 2004, A1, . Location in patent: Page 150
[4] Patent: WO2004/69805, 2004, A1, . Location in patent: Page 55
[5] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 66
[6] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 62-63
[7] Patent: WO2003/104236, 2003, A1, . Location in patent: Page 168-169
[8] Patent: CN106588937, 2017, A, . Location in patent: Paragraph 0196
[9] Patent: WO2004/814, 2003, A1, . Location in patent: Page 61; 62
[10] Patent: US2004/102472, 2004, A1, . Location in patent: Page 38
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  • [ 83664-33-9 ]
Reference: [1] Patent: EP1439175, 2004, A1, . Location in patent: Page 46-47
  • 53
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  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 881-86-7 ]
Reference: [1] Organic Letters, 2004, vol. 6, # 13, p. 2097 - 2100
  • 54
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  • [ 77992-44-0 ]
YieldReaction ConditionsOperation in experiment
96% at 20℃; for 13 h; Heating / reflux 1) 5-bromo-2-hydrazinopyridine; Hydrazine monohydrate (10 ml) was added to a solution of 2,5-dibromopyridine (10.0g) in pyridine (100ml) at room temperature, and the mixture was heated under reflux for 13 hours. After cooling with air, the reaction solvent was evaporated under reduced pressure. To the residue were added 0.5N aqueous sodium hydroxide and chloroform and phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 5-bromo-2-hydrazinopyridine (7.61 g, 96percent) as a solid. 1H-NMR (400 MHz, DMSO-d6)δ: 6.67 (1H, d, J = 9.0 Hz), 7.55 (1H, dd, J = 9.0, 2.4 Hz), 7.64 (1H, s), 8.00 (1H, d, J = 2.4 Hz). EI-MSm/z: 188 (M+).
94.8% at 110℃; for 2 h; To a solution of 2,5-dibromopyridine (10.50 g, 44 mmol) in 210 mL of pyridine was added hydrazine hydrate (80percent, 8.85 g, 176.4 mmol), and the mixture was heated to 110° C. and stirred further for 2 hours, then cooled to rt, and concentrated in vacuo. The residue was diluted with DCM (1500 mL). The resulted mixture was washed with aqueous NaOH solution (1 M, 350 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound as a gray solid (7.87 g, 94.8percent). MS (ESI, pos. ion) m/z: 188.0[M+H]+; 1H NMR (600 MHz, DMSO-d6): δ 8.03 (d, J=2.3 Hz, 1H), 7.67 (s, 1H), 7.59 (dd, J=8.9, 2.5 Hz, 1H), 6.69 (d, J=8.9 Hz, 1H), 4.16 (s, 2H).
89% With hydrazine hydrate In isopropyl alcohol for 12 h; Reflux A mixture of 2,5-dibromopyridine (3; 15.4 g, 65.0 mmol), hydrazine hydrate (30 mL), and propan-2-ol (30 mL) was refluxed for 12 h, and the excess hydrazine hydrate was removed under vacuum. The residue was suspended in cold H2O (50 mL), and the precipitate formed was collected by filtration and washed with ice cold H2O (2 × 15 mL). The obtained precipitate was recrystallized from EtOH to give off-white or pale beige crystals; yield: 10.89 g (89percent); mp 134–135 °C (EtOH) (Lit.20 mp 134–136 °C); Rf = 0.6 (CHCl3–EtOAc). IR (KBr): 3294, 3248, 3172, 2925, 2854, 1595, 1504, 1477, 989, 808 cm–1.1H NMR (CDCl3): δ = 3.80 (br s, 2 H, NH2), 5.95 (br s, 1 H, NH), 6.67 (d,J = 8.8 Hz, 1 H, H-3), 7.55 (dd, J1 = 8.8 Hz, J2 = 2.2 Hz, 1 H, H-4), 8.15 (d,J = 2.2 Hz, 1 H, H-6).13C NMR (CDCl3): δ = 107.8, 108.6, 139.5, 147.5, 159.6.MS (EI, 70 eV): m/z (percent) = 189 (96, [M (81Br)]+), 187 (100, [M (79Br)]+),159 (35), 157 (35), 117 (11), 92 (16), 78 (71), 64 (55), 51 (65), 50 (57).Anal. Calcd for C5H6BrN3: C, 31.94; H, 3.22; N, 22.35. Found: C, 32.06; H, 3.13; N, 22.46.
87%
Stage #1: With hydrazine In poly (ethylene glycol); water; iso-butanol for 49 h; Heating / reflux
Stage #2: for 0.5 h;
A mixture of 2,5-dibromopyridine (44.2 [G,] 0. [187MOLES),] hydrazine hydrate (55percent by weight, 105.7 mL, 1.87 mol), poly (ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is refluxed gently for 29 hours. The mixture is then cooled and stirred for 20 hours. To the resulting slurry, cold water (220 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3x) and dried in a vacuum-oven (40-45 [°C)] for 48 hours. The title compound (30.5 g, 87percent) is obtained as off- white flakes. A) [5-BROMO-PVRIDINE-2-YL-HVDRAZINE] A mixture of 2,5-dibromopyridine (44.2 [G,] 0. [187MOLES),] hydrazine hydrate (55percent by weight, 105.7 mL, 1.87 mol), poly (ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is refluxed gently for 29 hours. The mixture is then cooled and stirred for 20 hours. To the resulting slurry, cold water (220 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3x) and dried in a vacuum-oven (40-45 [°C)] for 48 hours. The title compound (30.5 g, 87percent) is obtained as off- white flakes. A) [5-BROMO-PVRIDINE-2-VL-HVDRAZINE] A mixture of 2,5-dibromopyridine (44.2 g, 0. [187MOLES),] hydrazine hydrate [(55percent] by weight, 105.7 mL, 1.87 mol), poly (ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is refluxed gently for 29 hours. The mixture is cooled and stirred for 20 hours. To the resulting slurry, cold water (220.0 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3x) and dried in a vacuum-oven [(40-45°C)] for 48 hours. The title compound (30.5 g, 87percent) may be obtained as off-white flakes.A) [5-BROMO-PVRIDINE-2-VL-HVDRAZINE] A mixture of 2,5-dibromopyridine (44.2 g, 0. [187MOLES),] hydrazine hydrate [(55percent] by weight, 105.7 mL, 1.87 mol), poly (ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is [REFLUXED] gently for 29 hours. The mixture is cooled and stirred for 20 hours. To the resulting slurry, cold water (220.0 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3x) and dried in a vacuum-oven (40-45 [°C)] for 48 hours. The title compound (30.5 g, 87percent) may be obtained as off-white flakes.A) [5-BROMO-PVRIDINE-2-VL-HVDRAZINE] A mixture of 2,5-dibromopyridine (44.2 g, 0.187 mol), hydrazine hydrate (55percent by weight, 105.7 mL, 1.87 mol), poly (ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen was [REFLUXED GENTLY] for 29 hours. The mixture was cooled and stirred for 20 hours. To the resulting slurry, cold water (220.0 mL) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3x) and dried in a vacuum-oven (40-45 [°C)] for 48 hours. The title compound (30.5 g, 87percent) was obtained as off-white flakes.
87%
Stage #1: With hydrazine In H20; poly (ethylene glycol); iso-butanol for 49 h; Heating / reflux
Stage #2: for 0.5 h;
A mixture of 2,5-dibromopyridine (44.2 g, 0. [187MOLES),] hydrazine hydrate [(55percent] by weight, 105.7 mL, 1.87 mol), poly (ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is refluxed gently for 29 hours. The mixture is cooled and stirred for 20 hours. To the resulting slurry, cold water (220.0 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3x) and dried in a vacuum-oven [(40-45°C)] for 48 hours. The title compound (30.5 g, 87percent) may be obtained as off-white flakes.
87% With hydrazine In water; iso-butanol; poly(ethylene glycol) for 49 h; Heating / reflux A 12L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen [BUBBLER] and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1. [87MOLES),] hydrazine hydrate (55percent wt., 1057 ml, [18.] 7 moles), poly (ethylene glycol) (average Mn about 300,1. 87 L), 2-butanol (373 [ML)] and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water [(2.] 2L) was added. The slurry was stirred for an additional [30] minutes and filtered. The cake was washed with cold water (3 x [200] [ML)] and dried in a vacuum-oven [(40°C)] for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87percent). GCMS (m/z): 187 (M+). [HAPOS;NMR] (400 MHz, [CDCI3)] : 8 8.14 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.7/2. 0 Hz, 1 H), 6.66 (d, J=8.7Hz, [1 H),] 5.89 (brs, 1 H), 3.65 (brs, 2H).
87% With hydrazine In water; iso-butanol; poly(ethylene glycol) for 49 h; Heating / reflux A 12L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen bubbler and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1.87 moles), hydrazine hydrate (55percent wt., 1057 ml, 18.7 moles), poly(ethylene glycol) (average Mn about 300, 1.87 L), 2-butanol (373 ml) and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water (2.2L) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3.x.200 ml) and dried in a vacuum-oven (40° C.) for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87percent). [0178] GCMS(m/z): 187 (M+). H1 NMR (400 MHz, CDCl3): δ8.14 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.7/2.0 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.89 (brs, 1H), 3.65 (brs, 2H).; A mixture of 2,5-dibromopyridine (44.2 g, 0.187 moles), hydrazine hydrate (55percent by weight, 105.7 mL, 1.87 mol), poly(ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is refluxed gently for 29 hours. The mixture is cooled and stirred for 20 hours. To the resulting slurry, cold water (220.0 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3.x.) and dried in a vacuum-oven (40-45° C.) for 48 hours. The title compound (30.5 g, 87percent) may be obtained as off-white flakes
87% With polyethylene glycol; hydrazine In water; iso-butanol for 49.5 h; Heating / reflux Preparation 1 5-BROMO-PYRIDIN-2-YL-HYDRAZINE A 12 L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen bubbler and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1.87 moles), hydrazine hydrate (55percent wt., 1057 ml, 18.7 moles), poly(ethylene glycol) (average Mn about 300, 1.87 L), 2-butanol (373 ml) and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water (2.2 L) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3.x.200 ml) and dried in a vacuum-oven (40° C.) for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87percent). [0186] GCMS(m/z): 187 (M+). H1 NMR (400 MHz, CDCl3): δ 8.14 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.7/2.0 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.89 (brs, 1H), 3.65 (brs, 2H).
87% With polyethylene glycol; hydrazine In water; iso-butanol for 29 h; Heating / reflux A) 5-Bromo-pyridine-2-yl-hydrazine [0213] A mixture of 2,5-dibromopyridine (44.2 g, 0.187 moles), hydrazine hydrate (55percent by weight, 105.7 mL, 1.87 mol), poly(ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is refluxed gently for 29 hours. The mixture is cooled and stirred for 20 hours. To the resulting slurry, cold water (220.0 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3.x.) and dried in a vacuum-oven (40-45° C.) for 48 hours. The title compound (30.5 g, 87percent) may be obtained as off-white flakes.
87% With poly(ethylene glycol); hydrazine In water; iso-butanol for 49.5 h; Heating / reflux A 12L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen bubbler and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1.87 moles), hydrazine hydrate (55percent wt., 1057 ml, 18.7 moles), poly(ethylene glycol) (average Mn about 300, 1.87 L), 2-butanol (373 ml) and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water (2.2L) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3.x.200 ml) and dried in a vacuum-oven (40° C.) for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87percent). [0178] GCMS(m/z): 187 (M+). H1 NMR (400 MHz, CDCl3): δ 8.14 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.7/2.0 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.89 (brs, 1H), 3.65 (brs, 2H). A) 5-Bromo-pyridine-2-yl-hydrazine [0204] A mixture of 2,5-dibromopyridine (44.2 g, 0.187 moles), hydrazine hydrate (55percent by weight, 105.7 mL, 1.87 mol), poly(ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen is refluxed gently for 29 hours. The mixture is then cooled and stirred for 20 hours. To the resulting slurry, cold water (220 mL) is added. The slurry is stirred for an additional 30 minutes and filtered. The cake is washed with cold water (3.x.) and dried in a vacuum-oven (4045° C.) for 48 hours. The title compound (30.5 g, 87percent) is obtained as off-white flakes.
87% With polyethylene glycol; hydrazine In water; iso-butanol for 49.5 h; Heating / reflux A 12 L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen bubbler and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1.87 moles), hydrazine hydrate (55percent wt., 1057 ml, 18.7 moles), poly(ethylene glycol) (average Mn about 300, 1.87 L), 2-butanol (373 ml) and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water (2.2 L) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3200 ml) and dried in a vacuum-oven (40 C.) for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87percent). [0085] GCMS(m/z): 187 (M+). H1 NMR (400 MHz, CDCl3): d 8.14 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.7/2.0 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.89 (brs, 1 H), 3.65 (brs, 2H).
87% With poly(ethylene glycol); hydrazine In water; iso-butanol for 49 h; Heating / reflux A 12L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen bubbler and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1.87 moles), hydrazine hydrate (55percent wt., 1057 ml, 18.7 moles), poly(ethylene glycol) (average M, about 300, 1.87 L), 2-butanol (373 ml) and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water (2.2 L) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3.x.200 ml) and dried in a vacuum-oven (40° C.) for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87percent). [0187] GCMS(m/z): 187 (M+). H1 NMR (400 MHz, CDCl3): δ 8.14 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.7/2.0 Hz, 1 H), 6.66 (d, J=8.7 Hz, 1H), 5.89 (brs, 1H), 3.65 (brs, 2H).A) 5-Bromo-pyridine-2-yl-hydrazine [0212] A mixture of 2,5-dibromopyridine (44.2 g, 0.187 mol), hydrazine hydrate (55percent by weight, 105.7 mL, 1.87 mol), poly(ethylene glycol) (187.0 mL), 2-butanol (37.3 mL) and water (187.0 mL) under nitrogen was refluxed gently for 29 hours. The mixture was cooled and stirred for 20 hours. To the resulting slurry, cold water (220.0 mL) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3.x.) and dried in a vacuum-oven (40-45° C.) for 48 hours. The title compound (30.5 g, 87percent) was obtained as off-white flakes.
62% With hydrazine In pyridine at 85℃; for 48 h; A mixture of 2,5-Dibromo-pyridine (13 g, 55.1 MMOL) and hydrazine (13 mL, 414 MMOL) in pyridine (13 mL) was heated at 85 °C for 48 hours. The reaction was cooled and concentrated in vacuo. The residue was triturated in 1N NAOH (20 mL) and toluene (20 mL). The solid was filtered, washed with water, and dried to give the above named compound (6.43 g, 62percent).; A mixture of 2,5-Dibromo-pyridine (13 g, 55.1 MMOL) and hydrazine (13 mL, 414 MMOL) in pyridine (13 mL) was heated at 85 C for 48 hours. The reaction was cooled and concentrated in vacuo. The residue was triturated in 1 N NAOH (20 mL) and toluene (20 mL). The solid was filtered, washed with water, and dried to give the above named compound (6.43 g, 62percent); A mixture of 2,5-Dibromo-pyridine (13 g, 55.1 MMOL) and hydrazine (13 mL, 414 MMOL) in pyridine (13 mL) was heated at 85 oc for 48 hours. The reaction was cooled and concentrated in vacuo. The residue was triturated in 1 N NAOH (20 mL) and toluene (20 mL). The solid was filtered, washed with water, and dried to give the above named compound (6.43 G, 62percent).
59% for 48 h; Reflux To a solution of 2,5-dibromopyridine (15 g, 64 mmol) was added NH2NH2H2O (20 mL). The reaction mixture was refluxed for 2 days. The solvent was removed under reduced pressure, and the crude product was dissolved in DCM (200 mL) and washed with water and brine and dried over Na2SO4. The solvent was removed and the crude product was purified on a silica gel column using Biotage Isolera One purification system employing an EtOAc/n-heptane gradient (20/80=>50/50) to afford the title compound (5.1 g, 59percent based on starting material recovery).1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.56 (d, 1H), 6.69 (d, 1H), 6.04 (brs, 1H), 3.7 (brs, 2H).
8 g With hydrazine hydrate In butan-1-ol at 115℃; for 6 h; To a solution of 2,5-dibromopyridine (10 g, 42 mmol) in 1-butanol (50 mL), hydrazine hydrate (80percent, 13 mL, 211 mmol) is added at room temperature. After 6 hours at 115° C., the mixture is concentrated to around 15 mL. The white solid is formed and collected by filtration, washed by 30 mL cold water. After dried in the air overnight, Compound 2 (8.0 g) is obtained as an off-white solid.

Reference: [1] Patent: EP1698626, 2006, A1, . Location in patent: Page/Page column 25
[2] Patent: US2014/134133, 2014, A1, . Location in patent: Paragraph 0448
[3] Synthesis (Germany), 2015, vol. 47, # 20, p. 3169 - 3178
[4] Patent: WO2004/20440, 2004, A1, . Location in patent: Page 39,46,50,55,60
[5] Patent: WO2004/20440, 2004, A1, . Location in patent: Page 50
[6] Patent: WO2004/20438, 2004, A2, . Location in patent: Page 45
[7] Patent: US2004/77682, 2004, A1, . Location in patent: Page 17; 21
[8] Patent: US2004/87615, 2004, A1, . Location in patent: Page 16
[9] Patent: US2004/87615, 2004, A1, . Location in patent: Page 20
[10] Patent: US2004/92547, 2004, A1, . Location in patent: Page/Page column 16-17; 20-21
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[12] Patent: US2004/157877, 2004, A1, . Location in patent: Page 17; 21
[13] Patent: WO2006/18735, 2006, A2, . Location in patent: Page/Page column 33
[14] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 469 - 473
[15] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 4, p. 1071 - 1077
[16] Patent: WO2004/72072, 2004, A1, . Location in patent: Page 50; 55; 82-83
[17] Patent: US2011/280808, 2011, A1, . Location in patent: Page/Page column 77
[18] Journal of Medicinal Chemistry, 2005, vol. 48, # 18, p. 5728 - 5737
[19] Patent: US2002/77487, 2002, A1,
[20] Patent: US4260767, 1981, A,
[21] Patent: US9012643, 2015, B2, . Location in patent: Paragraph 0423; 0424
[22] Patent: US2015/218380, 2015, A1, . Location in patent: Paragraph 0176
[23] Patent: WO2017/46318, 2017, A1, . Location in patent: Page/Page column 32
  • 55
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  • [ 7803-57-8 ]
  • [ 77992-44-0 ]
Reference: [1] Patent: WO2015/150564, 2015, A1, . Location in patent: Page/Page column 57
  • 56
  • [ 624-28-2 ]
  • [ 56-35-9 ]
  • [ 1448262-76-7 ]
  • [ 59020-10-9 ]
YieldReaction ConditionsOperation in experiment
70% With magnesium; ethylene dibromide In tetrahydrofuran at 35℃; for 1 h; Sonication; Inert atmosphere General procedure: A mixture of magnesium turnings (0.027g, 1.1mmol), bromobenzene (0.15g, 1mmol), bis(tri-n-butyltin) oxide (0.60g, 1mmol) and 1,2-dibromoethane (0.094g, 0.5mmol) as initiator in dry THF (5mL) was sonicated for 1h in an ultrasonic cleaning bath at around 35°C, with monitoring of the reaction by TLC. Once the reaction finished, aqueous saturated NH4Cl solution (40mL) was added and extracted with ethyl acetate (3×20mL). The combined extracts were washed with brine (60mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography with silica gel doped with 10percent of KF to retain the tri-n-butyltin bromide formed during the reaction.
Reference: [1] Journal of Organometallic Chemistry, 2013, vol. 741-742, # 1, p. 24 - 32
  • 57
  • [ 624-28-2 ]
  • [ 1461-22-9 ]
  • [ 1448262-76-7 ]
  • [ 59020-10-9 ]
YieldReaction ConditionsOperation in experiment
58% With magnesium; ethylene dibromide In tetrahydrofuran at 35℃; for 1 h; Sonication; Inert atmosphere General procedure: A mixture of magnesium turnings (0.036g, 1.5mmol), bromobenzene (0.15g, 1mmol), tri-n-butyltin chloride (0.49g, 1.5mmol) and 1,2-dibromoethane (0.094g, 0.5mmol) as initiator in dry THF (5mL) was sonicated for 1h in an ultrasonic cleaning bath at around 35°C, with monitoring of the reaction by TLC. Once the reaction finished, aqueous saturated NH4Cl solution (40mL) was added and extracted with ethyl acetate (3×20mL). The combined extracts were washed with brine (60mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the product was isolated by column chromatography with silica gel doped with 10percent of KF to retain tri-n-butyltin halides formed during the reaction. 4 (0.286, 0.78mmol, 78percent) eluted with 98:2 (hexane/diethyl ether).
Reference: [1] Journal of Organometallic Chemistry, 2013, vol. 741-742, # 1, p. 24 - 32
  • 58
  • [ 624-28-2 ]
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 29682-15-3 ]
YieldReaction ConditionsOperation in experiment
58% With triethylamine In acetonitrile at 60℃; for 16 h; 2,5-Dibromopyridine (9.5 g, 40. 10MMOL), PDCL2 (PPH3) 2 (844 mg), triethylamine (8. 36 mL), methanol (38 mL), and acetonitrile (114 mL) were combined, heated under carbon monoxide atmosphere (75 psi) at 60oC for 16 hours and concentrated. The residue was purified by flash chromatography eluting with 25percent ethyl acetate in hexane. The title compound (5.02 g) was obtained at 58percent yield. MS (DCI/MH3) M/Z : 215.95 (M+H) +. LH NMR (500 MHz, DMSO- D6) 8 ppm 3.91 (s, 3 H) 8.00 (d, J=8.11 Hz, 1 H) 8. 27 (dd, J=8.42, 2.49 Hz, 1 H) 8.86 (d, J=1.56 Hz, 1 H)
Reference: [1] Synthetic Communications, 1997, vol. 27, # 3, p. 515 - 520
[2] Patent: WO2004/80973, 2004, A1, . Location in patent: Page 182-183
[3] Patent: US2003/236251, 2003, A1, . Location in patent: Page 29
[4] Dalton Transactions, 2011, vol. 40, # 29, p. 7534 - 7540
  • 59
  • [ 624-28-2 ]
  • [ 107-31-3 ]
  • [ 29682-15-3 ]
YieldReaction ConditionsOperation in experiment
55%
Stage #1: With trimethylsilylmethyllithium In toluene at -78 - 0℃; for 0.5 h;
Stage #2: for 3 h;
Stage #3: With iodine; potassium carbonate In toluene at 20℃; for 18 h;
General procedure: N,N-Dimethylaminoethanol (0.85 ml, 8.5 mmol, 1 equiv.) and(trimethylsilyl)methyllithium 1 M (25.3 ml, 25.3 mmol, 3 equiv.)was added dropwise to 25 ml of dry toluene at 0 °C and the solutionwas stirred for 30 min to form TMSCH2Li-LiDMAE (in situ). Then, Asolution of 2,5-dibromopyridine 1 (2 g, 8.5 mmol, 1 equiv.) in 9 mlof dry toluene was added dropwise. The reaction mixture wasstirred for 30 min, cooled to 78 °C and added methyl formate(5.2 ml, 85 mmol, 10 equiv.) or ethyl formate (6.9 ml, 85 mmol,10 equiv.) in 10 ml of toluene. The reaction mixture stirred for 3 h,and I2 (6.4 g, 25.5 mmol, 3 equiv.), K2CO3 (5.8 g, 42.5 mmol, 5 equiv.)and 20 ml methanol or ethanol were added. The mixture wasstirred at room temperature for 18 h and added 10 ml of a sat.aqueous Na2SO3 solution.Water (10 ml)was added and the mixtureextracted with dichloromethane (3x40 ml), washed with water(1 x 25 ml) and brine (1 x 25 ml). The residue was purified bysilica-gel flash column chromatography (eluent: heptane/diethylether 2: 1) to obtain 2a-b.4.2.2.1. Methyl 5-bromopicolinate (2a). From 1 (2 g) gave 2a(997 mg, 55percent); white solid; >99percent purity; mp 103-104 °C (reported98.0-102.0 °C [30a]); 1H NMR (600 MHz, CDCl3)δ 8.77 (dd, J = 2.2,0.71 Hz, 1H, H2), 8.01 (dd, J = 8.3, 0.8 Hz, 1H, H5), 7.98 (dd, J = 2.3,2.2 Hz, 1H, H6), 3.99 (s, 1H, CH3);13C NMR (100 MHz, CDCl3):δ 165.0(C]O, C-7), 151.0(C-2), 146.3(C-4), 139.7(C-6), 126.3(C-5),125.1(C-1); HRMS (ESI) m/z [M+H]+ calcd for C7H7BrNO2 +215.9660,found 215.9659. Data was in accordance with those reported [30a].
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
  • 60
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  • [ 29682-15-3 ]
Reference: [1] Tetrahedron, 2005, vol. 61, # 45, p. 10748 - 10756
[2] Journal of Organic Chemistry, 2001, vol. 66, # 2, p. 605 - 608
  • 61
  • [ 624-28-2 ]
  • [ 68-12-2 ]
  • [ 31181-90-5 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With n-butyllithium In hexane; toluene at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h; Inert atmosphere
This compound was prepared according to general procedure C bytreating 2,5-dibromopyridine (237 mg, 1 mmol) with DMF (115 μL,1.5 mmol). The crude product was purified by flash chromatography(hexane/ethyl acetate 10:1) to give the product 27b as an off-brownsolid (149 mg, 80percent); Rf (hexane/ethyl acetate 8:1): 0.45; 1H NMR(400 MHz, CDCl3): δ 10.03 (1H, s), 8.85 (1H, dd, J=0.8, 2.0 Hz), 8.02(1H, ddd, J=0.8, 2.0, 8.0 Hz), 7.85 (1H, dd, J=0.8, 8.0 Hz); 13C NMR(100 MHz, CDCl3): δ 192.4, 151.7, 151.3, 140.0, 126.3, 122.8. Thespectroscopic data matched that reported in the literature.
74.2%
Stage #1: With n-butyllithium In hexane; dichloromethane at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃;
Example 41; 2-({3-[S-(2-Fluoropheny])pyridin-2-yl]propanoyl}amino)thiophene-3-carboxylic Acid; a) 5-Bromopyridine-2-carbaldehyde; A solution of 2,5-dibromopyridine (9.48g, 40 mmol) in methylene chloride (100 mL) was cooled to -78 0C , and π-butyllithium (1.60 M in hexane, 25.0 mL, 40 mmol ) was then added to the solution. After stirring at -78 0C for 30 min, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The mixture was allowed to slowly warm up to room temperature and stirring was continued for one more hour at room temperature. The reaction was quenched by addition of aqueous NH4Cl. Ethyl acetate was used to extract the product, and the extracts were dried, filtered and concentrated to give 8.50g (74.2percent) of crude product, which was used directly for next step.
52%
Stage #1: With n-butyllithium In hexane; toluene at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 7 h;
Example 5 -- Synthesis of Compound 109 A solution of 2,5-dibromopyridine 8 (25 g, 105.5 mmol) in toluene (1.24 L) was cooled to -78 °C before being treated dropwise with a 2.5 M solution of n-butyl lithium (n-BuLi) in hexane (50.6 mL, 126.6 mmol) at -78 °C. The resulting reaction mixture was stirred at -78 °C for 1 hr before being treated with anhydrous DMF (11.6 g, 12.2 mL, 158.0mmol) at-78 °C. The reaction mixture was stirred at -78 °C for an additional 1 hr before being gradually warmed to room temperature for 6 hr. When TLC and HPLC showed that the reaction was complete, the reaction mixture was quenched with H2O (200 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic extracts were then washed with H2O (2 x 200 mL) and saturated aqueous NaCl (100 mL) and dried over magnesium sulfate (MgS04). The solvents were then removed in vacuo, and the residual pale-yellow oil was purified by flash column chromatography (0-15percent EtOAc-hexane gradient elution) to afford the desired 5-bromo-pyridine-2-carbaldehyde 9 (10.2 g, 52percent yield ) as pale-yellow solids.
45% With n-butyllithium In toluene at -78 - -10℃; for 6 h; Following general procedure of Wang et al. [35], a solution of BuLi (2.5 M in hexanes, 10.0 ml, 25.3 mmol) was slowly added to a solution of 2,5-dibromopyridine (5.0 g, 21 mmol) in dry toluene (250 ml) at −78 °C and the mixture was stirred for 5 h. Next, dry DMF (2.15 ml, 27.6 mmol) was added. After stirring for 1 h at −78 °C, the solution was warmed up to −10 °C and the reaction was quenched with saturated NH4Cl aqueous solution. The organic phase was separated and the aqueous phase was washed twice with ethyl acetate. All organic fractions were collected, dried over MgSO4 and the solvent was removed by rotary evaporation. Column chromatography (silica gel, hexane/ethyl acetate 15:1) produced pure 1 (1.8 g, 45percent). All characterization is consistent with the literature values.
31%
Stage #1: With n-butyllithium In toluene at -78℃;
Stage #2: at -78 - 20℃;
Synthesis of Compound 1038A solution of 2,5-Dibromo-pyridine (22.2 g, 93.7 mmol, 1.0 equiv.) in toluene (1.2 L) was treated with nBuLi (70.25 ml, 112.4 mmol, 1.2 equiv.) dropwise at -78° C. The resulting solution was stirred at -78° C. for about 30 minutes, and DMF (11 ml, 141 mmol, 1.5 equiv.) was added. The reaction solution was warmed up gradually to RT and then stirred overnight. When TLC and MS showed the reaction was complete, the reaction mixture was concentrated in vacuo, and the residue was directly purified by column chromatography (SiO2, 10-30percent EtOAc/Hexanes gradient elution) to afford 5-Bromo-pyridine-2-carbaldehyde (1038, 5.45 g, 31percent yield) as yellowish white solid. For 1038: C6H4BrNO, LCMS (EI) m/e 187 (M++H).

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[5] Tetrahedron Letters, 2000, vol. 41, # 22, p. 4335 - 4338
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[9] Chemistry - A European Journal, 2008, vol. 14, # 17, p. 5313 - 5328
[10] Patent: US2010/234615, 2010, A1, . Location in patent: Page/Page column 49
[11] Journal of Organic Chemistry, 2003, vol. 68, # 26, p. 9907 - 9915
[12] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4048 - 4052
[13] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1407 - 1412
[14] Patent: EP2017275, 2009, A1, . Location in patent: Page/Page column 167
[15] Patent: WO2004/814, 2003, A1, . Location in patent: Page 70
[16] Patent: WO2005/14588, 2005, A1, . Location in patent: Page/Page column 58-59
[17] Journal of the American Chemical Society, 2009, vol. 131, # 40, p. 14508 - 14520
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[19] Angewandte Chemie - International Edition, 2013, vol. 52, # 25, p. 6464 - 6467[20] Angew. Chem., 2013, vol. 125, # 25, p. 6592 - 6595,4
[21] Journal of the American Chemical Society, 2013, vol. 135, # 38, p. 14052 - 14055
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Reference: [1] Organic Letters, 2004, vol. 6, # 26, p. 4905 - 4907
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  • [ 65873-72-5 ]
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[2] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
  • 64
  • [ 624-28-2 ]
  • [ 68-12-2 ]
  • [ 88139-91-7 ]
YieldReaction ConditionsOperation in experiment
59.2%
Stage #1: With n-butyllithium In hexane; toluene at -78℃; for 2 h;
Stage #2: at -78℃; for 0.166667 h;
Manufacturing Example 54-1-1 (5-Bromo-pyridin-2-yl)-methanol; To a toluene (300 mL) solution of 2,5-dibromopyridine (10.0 g, 42.2 mmol) was added dropwise n-butyl lithium (2.55 M n-hexane solution, 18.2 mL, 46.4 mmol) on a dry ice-ethanol bath (-78° C.) under nitrogen atmosphere, which was stirred for 2 hours at -78° C. N,N-dimethylformamide (3.7 g, 50.6 mmol) was then added dropwise thereto and stirred for 10 minutes at -78° C. Sodium borohydride (3.20 g, 84.4 mmol) and methanol (20.0 mL) were then added and stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1-->2:1) to obtain the title compound (4.70 g, 59.2percent).1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.54 (2H, d, J=5.6 Hz), 5.28 (1H, t, J=5.6 Hz), 7.44-7.47 (1H, m), 8.03-8.05 (1H, m), 8.59-8.60 (1H, m).
Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 22, p. 4335 - 4338
[2] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 101
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 21, p. 5147 - 5160
[4] Patent: EP2301930, 2016, B1, . Location in patent: Paragraph 0063
  • 65
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  • [ 88139-91-7 ]
Reference: [1] Chemistry - A European Journal, 2006, vol. 12, # 13, p. 3472 - 3483
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 25, p. 6464 - 6467[3] Angew. Chem., 2013, vol. 125, # 25, p. 6592 - 6595,4
[4] Journal of the American Chemical Society, 2013, vol. 135, # 38, p. 14052 - 14055
  • 66
  • [ 624-28-2 ]
  • [ 105170-27-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 23, p. 5835 - 5839
[2] Organic Letters, 2011, vol. 13, # 12, p. 3008 - 3011
[3] ChemPlusChem, 2017, vol. 82, # 5, p. 758 - 769
  • 67
  • [ 624-28-2 ]
  • [ 557-20-0 ]
  • [ 38749-90-5 ]
YieldReaction ConditionsOperation in experiment
38% With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 0 - 20℃; for 1.5 h; A suspension of 2,5-dibromo-pyridine (lOg, 42.21 mmol) and Pd(PPh3)4 (2.43g,2.11 mmol) in THF (100 mL) was added 1M Et2Zn (42.2 mL, 42.21 mmol) at 0 00 Thereaction mixture was stirred at 0 00 for 30 mm and then allowed to stir at RT for lh. Thereaction mixture was quenched with NaHCO3 solution and extracted with EtOAc. TheEtOAc layer was washed with water, brine, dried (Na2504), filtered and concentrated invacuo. The crude compound was purified by silica gel column chromatography eluting with 4percent EtOAc/pet-ether to obtain 5-bromo-2-ethyl-pyridine as a pale yellow liquid (3g, 38percent).R: 0.6 (10percent EtOAc/pet-ether).1H NMR (400MHz, CDCI3): O 8.57 (d, J= 2.4 Hz, 1H), 7.72-7.69 (m, 1H), 7.06 (d, J= 8.0 Hz, 1H), 2.81-2.75 (m, 2H), 1.29 (t, J= 8.0 Hz, 3H).
Reference: [1] Patent: WO2015/36759, 2015, A1, . Location in patent: Page/Page column 198
[2] Patent: US2014/275182, 2014, A1, . Location in patent: Paragraph 0374; 0375
[3] Patent: US8912227, 2014, B1, . Location in patent: Page/Page column 74
[4] Patent: WO2015/134038, 2015, A1, . Location in patent: Page/Page column 90
  • 68
  • [ 624-28-2 ]
  • [ 68-12-2 ]
  • [ 128071-75-0 ]
Reference: [1] Journal of Organometallic Chemistry, 1990, vol. 382, # 3, p. 319 - 332
  • 69
  • [ 624-28-2 ]
  • [ 123506-66-1 ]
Reference: [1] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
  • 70
  • [ 624-28-2 ]
  • [ 76053-45-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 71
  • [ 624-28-2 ]
  • [ 108281-79-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 4, p. 1071 - 1077
[2] Patent: US2014/134133, 2014, A1,
  • 72
  • [ 624-28-2 ]
  • [ 127-19-5 ]
  • [ 139042-59-4 ]
YieldReaction ConditionsOperation in experiment
47%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 1 h; Inert atmosphere
Stage #2: at -78℃; for 4 h; Inert atmosphere
Step 1:
Synthesis of 1-(6-bromopyridin-3-yl)ethanone
To a stirred solution of 2,5-dibromopyridine (1.0 g, 4.219 mmol) in diethyl ether (10 mL) at -78° C. was added n-Butyl lithium (2.0 mL, 5.0 mmol, 2.5M in hexane) under nitrogen and stirred for 1 h at the same temperature.
Dimethyl acetamide (0.58 g, 6.3 mmol) was then added drop wise to the reaction mixture, stirred for 4 h at -78° C.
Progress of reaction was monitored by TLC.
After completion reaction mass was quenched with ice cold water and partitioned between saturated NH4Cl solution and EtOAc.
The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to give 1-(6-bromopyridin-3-yl) ethanone (0.4 g, 47percent) as yellow solid
MS: 200.1 [M++1]
Reference: [1] Molecules, 2008, vol. 13, # 4, p. 818 - 830
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6763 - 6770
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 11, p. 3860 - 3874
[4] Patent: US2017/291894, 2017, A1, . Location in patent: Paragraph 0428
[5] Chemische Berichte, 1992, vol. 125, # 5, p. 1169 - 1190
  • 73
  • [ 624-28-2 ]
  • [ 139042-59-4 ]
Reference: [1] Patent: US5332757, 1994, A,
  • 74
  • [ 624-28-2 ]
  • [ 106984-91-2 ]
Reference: [1] Polyhedron, 2013, vol. 52, p. 755 - 760
  • 75
  • [ 624-28-2 ]
  • [ 667-27-6 ]
  • [ 77199-09-8 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: With copper In dimethyl sulfoxide at 20℃; for 1 h;
Stage #2: at 20℃; for 15 h;
SYNTHESIS OF INTERMEDIATE KETONE B2-(5-Bromopyridin-2-yl)- 1-(2,4-difluorophenyl)-2,2-difluoroethanone (B) To a suspension of copper powder (2.68 grams (g), 42.2 millimoles (mmol)) in dimethyl sulfoxide(DMSO; 35 milliliters (mL)) was added ethyl 2-bromo-2,2-difluoroacetate (2.70 mL, 21.10mmol), and the mixture was stirred for 1 hour (h) at room temperature (RT). 2,5-Dibromopyridine(2.50 g, 10.55 mmol) was then added, and stirring was continued for 15 h at RT. The reactionmixture was quenched with aqueous (aq) ammonium chloride (NH4C1) and extracted withdichloromethane (CH2C12 3 x 25 mL). The combined organic layers were washed with water (H20), washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure to afford the crude product mixture. Purification by column chromatography (eluting with ethyl acetate (EtOAc)/hexane) afforded the ethyl ester intermediate (2.40 g, 8.57mmol, 81percent) as a pale yellow oil. ‘H NMR (500 MHz, CDC13): ö 8.71 (s, 1H), 8.00 (d, J 9.0 Hz,1H), 7.64 (d, J= 9.0 Hz, 1H), 4.42-4.35 (m, 2H), 1.39-1.3 1 (m, 3H).
Reference: [1] Patent: WO2014/43376, 2014, A1, . Location in patent: Page/Page column 46; 47
  • 76
  • [ 624-28-2 ]
  • [ 109-94-4 ]
  • [ 77199-09-8 ]
YieldReaction ConditionsOperation in experiment
46%
Stage #1: With trimethylsilylmethyllithium In toluene at -78 - 0℃; for 0.5 h;
Stage #2: for 3 h;
Stage #3: With iodine; potassium carbonate In toluene at 20℃; for 18 h;
General procedure: N,N-Dimethylaminoethanol (0.85 ml, 8.5 mmol, 1 equiv.) and(trimethylsilyl)methyllithium 1 M (25.3 ml, 25.3 mmol, 3 equiv.)was added dropwise to 25 ml of dry toluene at 0 °C and the solutionwas stirred for 30 min to form TMSCH2Li-LiDMAE (in situ). Then, Asolution of 2,5-dibromopyridine 1 (2 g, 8.5 mmol, 1 equiv.) in 9 mlof dry toluene was added dropwise. The reaction mixture wasstirred for 30 min, cooled to 78 °C and added methyl formate(5.2 ml, 85 mmol, 10 equiv.) or ethyl formate (6.9 ml, 85 mmol,10 equiv.) in 10 ml of toluene. The reaction mixture stirred for 3 h,and I2 (6.4 g, 25.5 mmol, 3 equiv.), K2CO3 (5.8 g, 42.5 mmol, 5 equiv.)and 20 ml methanol or ethanol were added. The mixture wasstirred at room temperature for 18 h and added 10 ml of a sat.aqueous Na2SO3 solution.Water (10 ml)was added and the mixtureextracted with dichloromethane (3x40 ml), washed with water(1 x 25 ml) and brine (1 x 25 ml). The residue was purified bysilica-gel flash column chromatography (eluent: heptane/diethylether 2: 1) to obtain 2a-b
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
  • 77
  • [ 624-28-2 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 77199-09-8 ]
Reference: [1] Synthetic Communications, 1997, vol. 27, # 3, p. 515 - 520
[2] Dalton Transactions, 2011, vol. 40, # 29, p. 7534 - 7540
  • 78
  • [ 624-28-2 ]
  • [ 68-12-2 ]
  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 1 h;
40.0 g (168.8 mmol) of 2,5-dibromopyridine are placed in 2 L of anhydrous ethyl etherand maintained at -78 ° C. Slowly add 70.9 mL (177.2 mmol) of n-butyllithium (2.5 M,n-butyllithium) and keep for 1 hour. To the reaction mixture slowly add 14.3 mL (185.6mmol) of anhydrous dimethylformamide. The reaction mixture is maintained at -78 ° Cfor 1 hour and then slowly raised to room temperature. To the reaction was added a 1.0M aqueous hydrochloric acid solution (1.0 M aq. HCl) is added and stirred for 15minutes, and then the organic layer is separated. The resulting aqueous layer isextracted again with anhydrous ethyl ether. The resulting organic layers are combined,washed with water and dried over MgSO4. The organic layer was concentrated underreduced pressure to obtain 22.1 g (yield: 70percent) of a solid compound (intermediate (1)).
70%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 1 h;
40.0 g (168.8 mmol) of 2,5-dibromopyridine was added to the solution, Add 2 L of anhydrous ethyl ether and keep at -78 ° C. 70.9 mL (177.2 mmol) of n-butyllithium (2.5 M, n-butyllithium)Go slowly and keep for 1 hour.To the reaction mixture slowly add 14.3 mL (185.6 mmol) of anhydrous dimethylformamide. The reaction mixture was -78 up slowly to room temperature, the mixture was kept for 1 hour.100 mL of a 1.0 M aqueous hydrochloric acid solution (1.0 M aq. HCl) was added to the reaction mixture, followed by stirring for 15 minutes, followed by separation of the organic layer.The resulting aqueous layer is extracted again with anhydrous ethyl ether.The resulting organic layers are combined, washed with water and dried over MgSO4.The organic layer was concentrated under reduced pressure to obtain 22.1 g (yield: 70percent) of a solid compound (intermediate (7)).
70%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 1 h;
Stage #2: at -78℃; for 1 h;
40.0 g (168.8 mmol) of 2,5-dibromopyridine is placed in 2 L of anhydrous ethyl ether and the temperature is maintained at -78 ° C. Slowly add 70.9 mL (177.2 mmol) of n-butyllithium (2.5 M, n-butyllithium) and keep for 1 hour. To the reaction mixture slowly add 14.3 mL (185.6 mmol) of anhydrous dimethylformamide. The reaction mixture is maintained at -78 & lt; 0 & gt; C for 1 hour and then slowly raised to room temperature. 100 mL of a 1.0 M aqueous hydrochloric acid solution (1.0 M aq. HCl) was added to the reaction mixture, followed by stirring for 15 minutes, followed by separation of the organic layer. The resulting aqueous layer is extracted again with anhydrous ethyl ether. The resulting organic layers are combined, washed with water and dried over MgSO4. The organic layer was concentrated under reduced pressure to obtain 22.1 g (yield: 70percent) of a solid compound (intermediate (1)).
66%
Stage #1: With n-butyllithium In diethyl ether; hexane at -80℃; for 1 h; Inert atmosphere
Stage #2: at -80℃; for 1 h; Inert atmosphere
Stage #3: With hydrogenchloride In diethyl ether; hexane at 0℃; for 0.25 h; Inert atmosphere
To a suspension of 2,5-dibromopyridine (2.00 g, 8.44 mmol) in dry diethyl ether (25 mL) was added n-BuLi (3.55 mL, 8.87 mmol, 2,5 M solution in hexane) at -80°C under a nitrogen atmosphere. After stirring for 1 h at -80°C dry DMF (0.68 mg, 9.28 mmol) was added. After stirring for an additional hour at -80°C the reaction mixture was allowed to warm to 0°C and HCI (18.0 mL, 1 M) was added. After stirring for 15 minutes the phases were separated and aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with water (50 mL), brine (50 mL) and dried over MgS04. The organic phase was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica-gel using a mixture of hexane / ethyl acetate (8: 1) as eluent. White solid. Yield: 1.03 g, 66 percent. 1 H NMR (CDCI3, 500 MHz): δΗ (ppm) = 7.67 - 7.71 ppm (m, 1 H), 8.02 (dd, J = 8.2, 2.5 Hz, 1 H), 8.84 (dd, J = 2.5, 0.6 Hz, 1 H), 10.10 (s, 1 H); 13C NMR (CDCI3, 125 MHz): 5C (ppm) =129.0, 130.6, 137.5, 148.3, 152.5, 189.4; MS (ESI): m/z = 187.19 [M+H]+.
56%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.666667 h; Inert atmosphere
Stage #2: at -78℃; for 2 h;
6-bramonicotinaldeiwde (DL i To a stirred solution of 2, 5-dihromepyridine A (99 mL, 105.53 mmoi) in diethyl ether (250 mL) under argon atmosphere was added jj-BuLi (99 mL, 158.30 moL 1.6 M hexanes) at -78 °C and stiixed for 40 rain. Then DMF (16 mL, 211.06 mol) was added to the reaction mixture at -78 °C and stirred for another 2 h. The progress of the reaction was monitored by TLC. The reaction was quenched with aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 rnL), dried over anhydrous Na?SC>4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (elueii 20percent EtOAc Hexane) to afford compound DL (11 g. 59.13 mmoL 56percent) as paie yellow solid. H NMR (500 MHz, CDCl3): 5 10.07 (s, IH), 8.80 (s, IH), 8.00 (dd, J = 8.1, 2.3 Hz, IH), 7.66 (d, J= 8.1 Hz, 1H).
45%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃;
Stage #2: With ammonium chloride In diethyl ether; hexane
EXAMPLE 17 2-(2,4-Difluorophenyl)-l,l-difluoro-3-(lH-tetrazol-l-yl)-l-(5-(2,2,2- trifluoroethyl)pyridin-2-yl)propan-2-ol (17)To a stirred solution of 2,5-dibromopyridine (20 g, 84.1 mmol) in dry ether (400 mL) was added w-BuLi (1.6 M solution in hexane; 62.98 mL, 100.77 mmol) slowly at -78 °C. After being stirred for 45 min, DMF (12.28 g, 168.2 mmol) was added to the reaction mixture at - 78 °C, and the stirring was continued for another 2 h. After consumption of the starting material (by TLC), the reaction was quenched with saturated (satd) NH4C1 solution and extracted with EtOAc (4 x 500 mL). The combined organic extracts were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 15percent EtOAc/hexane) afforded aldehyde J (7.0 g, 37.8 mmol, 45percent) as a yellow solid. 1H NMR (500 MHz, CDC13): δ 10.09 (s, 1H), 8.83 (d, / = 2.0 Hz, 1H), 8.02 (dd, / = 8.0, 2.0 Hz, 1H), 7.68 (d, / = 8.0 Hz, 1H). MS (ESI): m/z 186 [M+].To a stirred solution of aldehyde J (1.0 g, 5.40 mmol) in 1,2-dimethoxyethane (DME; 10 mL) was added trimethyl(trifluoromethyl)silane (TMSCF3; 1.3 mL, 8.10 mmol) followed by cesium fluoride (CsF; 821 mg, 5.40 mmol) slowly at 0 °C under inert atmosphere. The resulting solution was stirred for 12 h at RT; progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was quenched with 1 N hydrochloric acid (HC1; 5.0 mL), stirred for 30 min and then extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with water and satd NaHC03 solution, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 20percent EtOAc/hexane) afforded compound K (0.6 g, 2.34 mmol, 43percent) as a yellow solid. 1H NMR (500 MHz, CDC13): δ 8.44 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.5, 2.0 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.09-5.06 (m, 1H), 3.27 (br s, 1H). MS (ESI): m/z 258 [M++2] . HPLC: 97.05percent.To a stirred solution of compound K (5.0 g, 19.53 mmol) in dry THF (60 mL) was added sodium hydride (NaH; 935 mg, 39.06 mmol) portionwise at 0 °C under inert atmosphere. After being stirred for 1 h, carbon disulfide (CS2; 2.35 mL, 39.06 mmol) was added to the reaction mixture drop wise, and the mixture was stirred for 1 h at 0 °C. To the resulting reaction mixture iodomethane (CH I; 2.43 mL, 39.06 mmol) was added at 0 °C, and then the mixture was stirred for 2 h at RT. After consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water and extracted with CH2C12 (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04 and concentrated under reduced pressure to afford dithionate L (7.0 g) that was used in the next step without any further purification. 1H NMR (400 MHz, CDC13): δ 8.47 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.0, 2.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.88 (q, J = 6.8 Hz, 1H), 2.61 (s, 3H). MS (ESI): m/z 348 [M++2] .To a stirred solution of compound L (7.0 g, crude) in dry toluene (40 mL) was added tributyltin stannane (Bu SnH; 10.5 mL, 30.34 mmol) followed by 2,2'- azobis(isobutyronitrile) (AIBN; 728 mg, 3.03 mmol) at RT under inert atmosphere. The reaction mixture was gradually heated up to 90 °C and stirred for 2 h. After consumption of the starting material (by TLC), the volatiles were removed under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 8percent EtOAc/Hexane) afforded compound M (3.0 g, 12.5 mmol, 61percent) as a pale-yellow liquid. This material contained a small amount of tin impurity and was used in the next step without any further purification. 1H NMR (400 MHz, CDC13): δ 8.31 (s, 1H), 7.51 (s, 2H), 3.36 (q, J = 10.4 Hz, 2H). MS (ESI): m/z 240 [M+] .To a stirred suspension of copper powder (3.17 g, 50 mmol) in DMSO (30 mL) was added ethyl 2-bromo-2,2-difluoroacetate (5.07 g, 25 mmol) and the mixture was stirred for 1 h at RT. To the resulting reaction mixture compound M (3.0 g, 12.5 mmol) was added, and the mixture was stirred for 12 h at RT. After completion of reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 8percent EtOAc/Hexane) afforded ester N (2.5 g, 8.83 mmol, 70percent) as a pale-yellow liquid. 1H NMR (400 MHz, CDC13): 58.58 (s, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 4.37 (q, J = 1.2 Hz, 2H), 3.46 (q, J = 10.4 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 284.2 [M++l] .To a stirred solution of l-bromo-2,4-difluorobenzene (818 mg, 4.24 mmol) in dry ether (15 mL) was added w-BuLi (1.6 M solution in hexane; 2.65 mL, 4.24 mmol) at -78 °C under inert atmosphere. After being stirred for 45 min, a solution of ester N (1.0 g, 3.53 mmol) in ether (5 mL) was added to the reaction mixture and stirring was continued for another 1 h at -78 °C. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution and extracted with CH2C12 (2 x 150 mL). The combined organic extracts were dried over anhydrous Na2S04 and concentrated under reduced pressure to afford ketone O (1.5 g) as brownish crude liquid. This crude material was used in the next step without any purification. 1H NMR (500 MHz, CDC13): δ 8.51 (s, 1H), 8.10-8.05 (m, 1H), 7.88-7.83 (m, 2H), 7.01-6.98 (m, 1H), 6.84-6.80 (m, 1H), 3.46 (q, J = 10.5 Hz, 2H).To a stirred solution of ketone O (0.9 g, crude) in ether (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (2.64 g, 25.64 mmol) in a 1 : 1 mixture of 10percent KOH solution (100 mL) and ether (100 mL) at 0 °C followed by separation and drying of the organic layer using KOH pellets] at 0 °C, and the mixture was stirred for 30 min. The resulting reaction mixture was stirred for 12 h at RT; progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (eluting with 10percent EtOAc/hexane) afforded the epoxide P (0.3 g, 0.82 mmol) as a brownish liquid. 1H NMR (400 MHz, CDC13): δ 8.59 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.40-7.34 (m, 1H), 6.85-6.80 (m, 1H), 6.76-6.70 (m, 1H), 3.48-3.40 (m, 3H), 2.97 (d, J = 4.8 Hz, 1H). MS (ESI): m/z 366 [M++l] .To a stirred solution of epoxide P (0.3 g, 0.82 mmol) in dry DMF (8 mL) was added 1H- tetrazole (113.4 mg, 1.23 mmol) followed by K2C03 (113.4 mg, 0.82 mmol) at RT under inert atmosphere. The reaction mixture was then stirred for 14 h at 65 °C. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 50percent EtOAc/hexane) afforded 17 (0.18 g, 0.41 mmol, 50percent) as a brownish liquid. 1H NMR (500 MHz, CDC13): δ 8.75 (s, 1H), 8.48 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.34-7.30 (m, 2H), 6.78-6.74 (m, 1H), 6.68-6.65 (m, 1H), 5.57 (d, J = 14.5 Hz, 1H), 5.13 (d, J = 14.5 Hz, 1H), 3.45 (q, J = 10.5 Hz, 2H). MS (ESI): m/z 434 [M+-l] . HPLC: 98.09percent.
30%
Stage #1: With n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at -78 - -30℃; for 1.5 h;
Example 38; 4-({3-[6-(2-Methoxyphenyl)pyridin-3-yl]propanoyl}amino)thiophene-3-carboxylic Acid; a) -Bromo-pyridineS-carbaldehyde; 2,5-Dibromopyridine (10.0 g, 0.0422 mol) was dissolved in the mixture solvent of ether (150.0 mL) and tetrahydrofuran (100.0 mL). The resulting solution was cooled to -780C, and ra-butyllithium (1.60 M in hexane, 26.4 mL) was added slowly. The reaction mixture was stirred at -78 0C for another 30 min before N,N-dimethylformamide (6.5 mL, 0.084 mol) was added slowly. The mixture was stirred at -78 0C for 1 hr and then warmed up to -300C over 30 min. LC-MS showed no starting material. The reaction was quenched with water. The organic phase was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified with 10percentEtOAC/Hexane on silica gel to afford the desired product as a white solid (2.4 g, 30percent). LC-MS,[M+1] 186.2;188.2.
28%
Stage #1: With n-butyllithium In tetrahydrofuran; diethyl ether at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 2 h;
Stage #3: With water In tetrahydrofuran; diethyl ether
Step A6-Bromo-pyridine-3-carbaldehyde. 2,5-Dibromopyridine 9.48 g (40 mmol) was dissolved in 60 mL of THF and 150 mL of anhydrous ether. After the solution was cooled to - 78 °C, 16 mL of n-butyllithium (2.5 M, 40 mmol) was slowly dropped through a syringe in 30 min. After being stirred at -78 °C for 30 minutes, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 30- 40percent EtOAc in hexane, 2.80g white solid was obtained (28percent yield), MS: (M+H)+ 186.0, 188.0.
11%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -90℃; for 0.0833333 h;
Stage #2: at -50℃; for 0.25 h;
To a cooled (-90°C) solution of 2,5-dibromopyridine (10 g) and THF (264 mL) was added, dropwise, nBuLi (16.9 mL of a 2.5 M solution in hexanes) and the resulting solution was stirred for 5 min. DMF (3.27 mL) was added dropwise and the resulting solution was warmed to - 50°C and stirred for 15 min at that temperature. The reaction solution was poured onto ice and extracted with EtOAc (3 * 75 mL). The combined EtOAc extracts were dried over MgSO4, filtered and evaporated to give 7.8 g of crude material which was purified by silica gel chromatography (4:1 hexane:EtOAc as eluant). After combining the desired fractions and evaporating the solvents, the desired aldehyde 5 was isolated as a solid (0.89 g) in 11 percent yield.

Reference: [1] Chemistry - A European Journal, 2003, vol. 9, # 20, p. 5011 - 5022
[2] Journal of Materials Chemistry C, 2017, vol. 5, # 35, p. 9053 - 9065
[3] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
[4] Patent: KR2017/72856, 2017, A, . Location in patent: Paragraph 0083-0086
[5] Patent: KR2017/58623, 2017, A, . Location in patent: Paragraph 0096-0099
[6] Patent: KR2017/58618, 2017, A, . Location in patent: Paragraph 0078-0081
[7] Patent: WO2012/52540, 2012, A1, . Location in patent: Page/Page column 59
[8] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6022 - 6032
[9] Tetrahedron Letters, 1999, vol. 40, # 5, p. 859 - 862
[10] Dalton Transactions, 2015, vol. 44, # 18, p. 8419 - 8432
[11] Patent: WO2017/117393, 2017, A1, . Location in patent: Page/Page column 165; 166
[12] Angewandte Chemie - International Edition, 2015, vol. 54, # 27, p. 7949 - 7953[13] Angew. Chem., 2015, vol. 127, # 27, p. 8060 - 8064,5
[14] Patent: WO2012/177603, 2012, A2, . Location in patent: Page/Page column 68-72
[15] Patent: WO2007/15744, 2007, A1, . Location in patent: Page/Page column 55-56
[16] Patent: WO2012/114223, 2012, A1, . Location in patent: Page/Page column 42
[17] Patent: EP1091956, 2004, B1, . Location in patent: Page 11
[18] Journal of Organic Chemistry, 2004, vol. 69, # 2, p. 250 - 262
[19] Organic Letters, 2004, vol. 6, # 26, p. 4929 - 4932
[20] Patent: EP1577288, 2005, A1, . Location in patent: Page/Page column 104
[21] Dalton Transactions, 2013, vol. 42, # 16, p. 5697 - 5705
  • 79
  • [ 624-28-2 ]
  • [ 50-00-0 ]
  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
56% With n-butyllithium In diethyl ether; acetone at -75℃; Inert atmosphere 2,5-dibromopyridine 4.7 g(20 mmol) is added to purified ether (150 ml) and sufficiently stirred.In order to remove the 5 bromes of 2,5-dibromopyridine in the substitution reaction of aldehyde, the reaction temperature is maintained at -75 ° C or less using an ice bath using liquid nitrogen / acetone. When the temperature of the reactor falls below -75 ,9.6 ml (24 mmol) of n-BuLi was slowly added thereto, followed by reaction for about 90 minutes. Then, 3.1 ml (40 mmol) of DMF was added and reacted for 24 hours to obtain a reaction product. The reactants were extracted with Eehtyl acetate (EA) and water, and the remaining water was removed using anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The extracted reaction product was purified by column chromatography (silica gel, n-hexane / ethyl acetate = 10: 1) and dried. 56percent yield: 1 H-NMR (CDCl 3, ppm):? 10.1 (s, 1 H); 8.8 (s, 1 H); 8.0 (d, 1 H); 7.2 (d, 1 H).
Reference: [1] Patent: KR101610226, 2016, B1, . Location in patent: Paragraph 0022-0023
  • 80
  • [ 624-28-2 ]
  • [ 693-04-9 ]
  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
66% With n-butyllithium; acetic acid In tetrahydrofuran; hexane; N,N-dimethyl-formamide; toluene WORKING EXAMPLE 5
Production of 6-bromo-3-formylpyridine
n-Butylmagnesium chloride (4.00 mmol) in 2.00M tetrahydrofuran solution (2.00 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.55M hexane (20 mL).
The mixture was stirred at 0° C. for 15 minutes to give a suspension.
The suspension was added to a mixture of toluene (15 mL) and tetrahydrofuran (10 mL) containing 2,5-dibromopyridine (2.37 g, 10.0 mmol) over a period of 10 minutes or more while keeping the temperature below -5° C. to give a dark orange solution.
The solution was stirred at 0° C. for 1.25 hours and then at 20° C. for one hour.
The solution was cooled to 0° C., and N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto.
After the mixture was stirred at 0° C. for 30 minutes, 1M aqueous acetic acid solution (20 mL) was added.
The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL).
The organic phases were combined, washed with saturated aqueous sodium chloride (15 mL), dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent.
The resultant residue was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (20:1, v/v) to give the title compound (1.229 g, 66percent yield) as a colorless solid. 1H-NMR(CDCl3) δppm:7.69 (1H, d, J=8.4 Hz), 8.02 (1H, dd, J=2.4, 8.4 Hz), 8.84 (1H, d, J=2.4 Hz), 10.10 (1H, s).
Reference: [1] Patent: US2003/130511, 2003, A1,
  • 81
  • [ 624-28-2 ]
  • [ 149806-06-4 ]
YieldReaction ConditionsOperation in experiment
64.8% With hydrogenchloride; n-butyllithium In N,N-dimethyl-formamide a.
2-Bromo-pyridine-5-carboxaldehyde.
To a suspension of 2,5-dibromopyridine (10.28 g, 0.043 mol) in dry ether (150 mL) cooled to -78° C. under argon was added dropwise a solution of n-BuLi (17.4 mL, 0.043 mol, 2.5M in hexanes) while maintaining an internal reaction temperature below -78° C.
The resulting dark red suspension was stirred for 30 min. and a solution of DMF (4.0 mL, 0.0521 mol) in 5 mL dry ether was added dropwise.
After 45 min. the bath was removed and the mixture was allowed to warm to RT.
The mixture was cooled to 0° C. and 1N HCl was added and stirred for 15 min.
The resulting layers were separated and the aqueous layer washed with ether (twice) and combined with the original organics.
The organics were washed with water, brine and dried (MgSO4).
The mixture was filtered and evaporated to give a solid that was purified by column chromatography (silica gel, CH2Cl2) to afford the product as a white solid, 5.23 g (64.8percent yield).
1H NMR (300 MHz; CDCl3) δ7.69 (d, J=8.0 Hz, 1 H), 8.03 (dd, J1=8.0 Hz, J2=2.0 Hz, 1 H), 8.84 (d, J=2.0 Hz, 1 H), 10.10 (s, 1 H).
Reference: [1] Patent: US2003/83357, 2003, A1,
  • 82
  • [ 624-28-2 ]
  • [ 1068-55-9 ]
  • [ 149806-06-4 ]
Reference: [1] Patent: US2002/120144, 2002, A1,
  • 83
  • [ 624-28-2 ]
  • [ 32117-82-1 ]
  • [ 149806-06-4 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 45, p. 7889 - 7892
  • 84
  • [ 624-28-2 ]
  • [ 107-31-3 ]
  • [ 149806-06-4 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 19, p. 4972 - 4975
  • 85
  • [ 624-28-2 ]
  • [ 162318-34-5 ]
Reference: [1] Canadian Journal of Chemistry, 2009, vol. 87, # 4, p. 533 - 538
[2] Chemical Communications, 2012, vol. 48, # 8, p. 1120 - 1122
[3] Inorganic Chemistry, 2018, vol. 57, # 7, p. 3602 - 3614
  • 86
  • [ 624-28-2 ]
  • [ 23719-80-4 ]
  • [ 579475-29-9 ]
YieldReaction ConditionsOperation in experiment
50%
Stage #1: With zinc(II) chloride In tetrahydrofuran at 20℃; for 2 h;
Stage #2: at 20℃;
2-Cyclopropyl-5-('4,4,5,5-tetramethyl-L3.2-dioxaborolan-2-vDpyridine0.5M Zinc chloride in THF (5.5 mL, 2.8 mmol) was added to a solution of 0.5M cyclopropylmagnesium bromide in THF (5.5 mL, 2.8 mmol) under argon. The solution was stirred at RT for 2 h at which time a slurry had formed. To this slurry was added in one portion 2,5-dibromopyridine (0.65 g, 2.8 mmol) and PdCl2 x dppf (0.041 g, 0.050 mmol). After a few minutes an exotherm was seen and the slurry became thicker, the exotherm subsided and the slurry was stirred at RT overnight. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ether. The ether phase was dried, filtered and concentrated, then re-dissolved in DCM and applied to a short plug of silica gel. The gel was washed with DCM and the washings were concentrated. The residue was taken up in ether and washed with 1.0M hydrochloric acid. The acidic water phase was made basic with 2.0M sodium hydroxide and the product was extracted back into ether. The combined ether phases were washed with brine, dried, filtered and concentrated to give 0.28 g (50percent) of 5-bromo-2-cyclopropylpyridine as a yellow oil. LC-MS mlz 197.9/199.9 (M+l); 1H-NMR(CDCl3) δ 8.48 (d, IH), 7.63 (dd, IH), 7.04 (d, IH), 1.99 (m, IH), 1.03-0.98 (m, 4H) ppm
Reference: [1] Patent: WO2006/65215, 2006, A1, . Location in patent: Page/Page column 28
[2] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 19, p. 2777 - 2782
  • 87
  • [ 624-28-2 ]
  • [ 203861-73-8 ]
  • [ 579475-29-9 ]
YieldReaction ConditionsOperation in experiment
100% at 70℃; for 3 h; To a solution 2,5-dibromopyridine[CAS 624-28-2, commercially available](5 g, 21 mmol) and Pd(PPh3)4 (244 mg, 1 mol percent) in THF (25 mL) was added cycloropylzinc chloride (0.4M in THF, 53 mL, 26 mmol), and the mixture was stirred under argon atmosphere at 70° C. for 3 h. Cooled to 23° C., poured into sat. NaHCO3-solution, extracted with ether, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by silica gel chromatography with heptane-EtOAc (9:1) to give the title compound as a colorless liquid (4.3 g, 103percent). MS (EI) 197 [(M)+] and 199 [(M+2)+].
Reference: [1] Patent: US2006/217387, 2006, A1, . Location in patent: Page/Page column 27
[2] Patent: WO2005/14002, 2005, A1, . Location in patent: Page/Page column 39
  • 88
  • [ 624-28-2 ]
  • [ 107-15-3 ]
  • [ 199522-66-2 ]
YieldReaction ConditionsOperation in experiment
98% at 100℃; for 15 h; 1 g (4.22 mmol) of 2,5-dibromopyridine was added to 10 mL of ethylenediamine, and the resulting solution was stirred at 100°C for 15 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove ethylenediamine. Thereafter, 50 mL of dichloromethane was added to dilute the concentrate, the diluted solution was washed with 30 mL of distilled water, and then 50 mL of dichloromethane was added to the collected distilled water to extract an organic layer therefrom, these processes were repeated twice more. The combined organic layers were dehydrated using anhydrous sodium sulfate, followed by concentration under reduced pressure, to obtain 0.89 g (4.12 mmol) of Compound XI as a light yellow liquid (yield: 98percent). [0103] 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 1.6 Hz, 1H), 7.45 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 6.33 (d, J = 8.8 Hz), 4.95 (brs, 1H), 3.34 (q, J = 6 Hz, 2H), 2.94 (t, J = 6 Hz, 2H)
98% at 100℃; for 15 h; Preparation of Compound XI 1 g (4.22 mmol) of 2,5-dibromopyridine was added to 10 mL of ethylenediamine, and the resulting solution was stirred at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove ethylenediamine. Thereafter, 50 mL of dichloromethane was added to dilute the concentrate, the diluted solution was washed with 30 mL of distilled water, and then 50 mL of dichloromethane was added to the collected distilled water to extract an organic layer therefrom, these processes were repeated twice more. The combined organic layers were dehydrated using anhydrous sodium sulfate, followed by concentration under reduced pressure, to obtain 0.89 g (4.12 mmol) of Compound XI as a light yellow liquid (yield: 98percent). [0114] 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1.6 Hz, 1H), 7.45 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 6.33 (d, J=8.8 Hz), 4.95 (brs, 1H), 3.34 (q, J=6 Hz, 2H), 2.94 (t, J=6 Hz, 2H)
Reference: [1] Patent: EP2692727, 2014, A2, . Location in patent: Paragraph 0102-0103
[2] Patent: US2014/179691, 2014, A1, . Location in patent: Paragraph 0112-0114
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 24, p. 4693 - 4705
[4] Patent: WO2017/106064, 2017, A1, . Location in patent: Page/Page column 60
  • 89
  • [ 624-28-2 ]
  • [ 67-64-1 ]
  • [ 290307-40-3 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With n-butyllithium In hexanes; toluene at -78 - 70℃;
Stage #2: for 0.5 h;
Stage #3: With ammonium chloride In hexanes; toluene
In a 2 L round-bottomed flask was mixed 2,5-dibromopyridine (54 g, 228 mmol) in toluene (600 ml) to give a colorless solution. The reaction was cooled to -78° C. and n-Butyllithium 2.5M hexanes (100 ml, 251 mmol) was added at a rate that the temperature did not exceed -70° C. The reaction was stirred for 30 minutes and then acetone (20.08 ml, 274 mmol) was added quickly. The reaction was stirred for 30 minutes and then quenched with saturated ammonium chloride. The organic layer was washed with brine, dried over sodium sulfate and solvent removed under reduced pressure. The crude residue was purified by column chromatography 20-50percent ethyl acetate/heptane to give 42.5 g of 2-(5-bromopyridin-2-yl)propan-2-ol in 86percent yield.In a 1 L round-bottomed flask was mixed compound 2-(5-bromopyridin-2-yl)propan-2-ol (10 g, 46.3 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (11.87 g, 50.9 mmol) in dioxane (300 ml). To this was added saturated sodium bicarbonate (150 mL). The reaction mixture was degassed via purging with a stream of nitrogen and then Pd(PPh3)4 (2.67 g, 2.314 mmol) was added. The mixture was heated to reflux becoming very thick then finally going into solution. The reaction was heated for 2 hours, cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and solvent removed under reduced pressure to give 2-(5-(5-amino-2-methylphenyl)pyridin-2-yl)propan-2-ol.The crude product from above was dissolved in dioxane (30 mL) and cooled to 0° C. Sulfuric acid was added to the solution through an addition funnel with manual stirring necessary at the beginning of addition, finally going to solution. The reaction was allowed to exotherm up to 30° C. and stirred for 30 minutes. Upon completion of the reaction as determined by LC/MS, the reaction was poured onto ice, extracted with ethyl acetate (2.x.200 mL) and the pH of the aqueous was adjusted to 9-10 by addition of 50percent sodium hydroxide solution. The mixture was then extracted with ethyl acetate, the organic was washed with brine and dried over sodium sulfate. After removal of solvent the crude product was isolated by column chromatography eluting 0-100percent ethyl acetate/heptane to give 4-methyl-3-(6-(prop-1-en-2-yl)pyridin-3-yl)aniline. Yield 9 g, 86percent over 2 steps.4-Methyl-3-(6-(prop-1-en-2-yl)pyridin-3-yl)aniline (9 g, 40.1 mmol) was dissolved in ethanol (100 mL) and 10percent palladium on carbon (0.5 g) was added. The mixture was hydrogenated at 30 psi for 2 hours. Filtration and concentration of the product afforded clean 3-(6-isopropylpyridin-3-yl)-4-methylaniline. Yield 8 g, 88percent
86%
Stage #1: With n-butyllithium In toluene at -78℃;
Stage #2: at -78 - 20℃;
Stage #3: With water; ammonium chloride In toluene
2,5-Dibromopyridine (1.04 g,4.39 mmol) was dissolved in toluene (22 mL) in a 100 mL round-bottomed flask. The mixture was cooled to -78 0C. n-Butyllithium (3.02 mL, 4.83 mmol) was added dropwise. The mixture was stirred 30 min, followed by the addition of acetone (2 mL). The mixture was stirred 40 min and then let warm to rt. The mixture was washed with ammonium chloride (5percent aq, 50 mL), water (50 mL) and then brine (50 rnL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by Biotage (16percent ethyl acetate in hexanes). Concentration of the desired fractions afforded the product (0.82 g, 3.78 mmol, 86 percent yield). MS (ESI) m/z 216.0 [M]+, 218.1 [M+2]+.
75%
Stage #1: With n-butyllithium In hexanes; toluene at -78℃; for 2 h;
Stage #2: at -78 - 20℃; for 1 h;
Stage #3: With ammonium chloride In hexanes; water; toluene
To a stirred solution of 2, 5-dibromopyridine (2.00 g, 8.44 mmol) in anhydrous toluene (100 mL) at-78 under nitrogen was slowly added a solution of .cents.BuLi (4.05 mL, 10.13 mmol, 2.5M in hexanes). After 2 h at-780C, acetone (806 pl, 10.98 mmol) was added. After stirring for 1 h, the reaction mixture was allowed to warm to 0 and was quenched with a saturated NH4CI. A two-phase system was formed; the organic layer was separated, washed with saturated NH4CI, H20 and brine, dried over anhydrous MgS04, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AcOEt/CH2CI2 : 20/80) to afford the title compound 54 (1.37 g, 6.34 mmol, 75percent yield) as a pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) No.(ppm) : ABX System (No.A = 7. 32, No.B = 7. 82, 8x = 8.58, JAB = 8.4 Hz, JBX = 2. 3 Hz, JAx = 0 Hz, 3H), 4.47 (bs, lH), 1.57 (s, 6H).
73%
Stage #1: With n-butyllithium In hexane; toluene at -78℃; for 0.5 h;
Stage #2: at -78℃; for 0.5 h;
(Example 159)
2-(S-{2-Fluoro-5-[3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl]phenyl}pyridin-2-yl)propan-2-ol (Compound No. 2-648)
(159a)
2-(5-Bromopyridin-2-yl)propan-2-ol
An n-butyllithium solution (1.6 M in hexane, 8.5 mL, 13 mmol) was added to a toluene solution (60 mL) of 2,5-dibromopyridine (2.6 g, 11 mmol) under a nitrogen atmosphere at -78°C. The resulting mixture was stirred at -78°C for 30 min, and then acetone (1.2 mL, 16 mmol) was added thereto. The resulting mixture was further stirred for 30 min. The reaction solution was returned to room temperature, and a saturated ammonium chloride aqueous solution was added thereto to terminate the reaction. After extraction with ethyl acetate, the organic layer was washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Biotage, eluting solvent; hexane/ethyl acetate) to obtain 1.7 g (yield: 73percent) of the title compound as a light yellow oily material. 1H-NMR (500 MHz, CDCl3) δ ppm: 8.58 (1H, d, J = 2.4 Hz), 7.82 (1H, dd, J = 2.4, 8.3 Hz), 7.31 (1H, d, J = 8.3 Hz), 4.42 (1H, s), 1.54 (6H, s). MS(ESI) m/z: 216 (M+H)+
63.1%
Stage #1: With n-butyllithium In hexane; toluene at -78℃; for 0.5 h;
Stage #2: at -78℃; for 0.5 h;
To a solution of 2,5-dibromopyridine (4 g, 16.89 mmol) in toluene (60 mL) at -78 °C, n- butyl lithium (2.5M in hexane) (10.13 mL, 25.3 mmol) was added dropwise, and the mixture was stirred for 30 min. Acetone (2 mL, 27.2 mmol) was then added to the reaction mixture, and the mixture was stirred for 30 min at -78 °C. The reaction mixture was allowed to warm to room temperature, aqueous ammonium chloride was added to the mixture, and the mixture was partitioned between ethyl acetate and water. Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 20percent ethyl acetate in hexanes to afford the title compound (2.4 g, 63.1percent) as a yellow oil. lH NMR (400 MHz, CDC13): δ 8.58 (d, J= 2.0 Hz, 1H), 7.82 (dd, J; = 2.0 Hz, J2 = 8.4 Hz, 1H), 7.32 (d, J= 8.8 Hz, 1H), 4.4 (s, 1H), 1.56 (s, 3H), 1.53 (s, 3H). ESI-MS m/z = 216 (M+H)+.
52%
Stage #1: With n-butyllithium In hexane; toluene at -78℃; for 0.333333 h;
Stage #2: at -78 - 20℃; for 0.666667 h;
INTERMEDIATE 502-(5-Bromopyridin-2-vD-propan-2-olTo a suspension of 2,5-dibromopyridine (1.5 g, 6.35 mmol) in toluene (33 mL) cooled to -78°C was added dropwise n-butyllithium (4.5 mL of a 1.6M solution in hexanes, 7.2 mmol). The mixture was stirred for 20 minutes with cooling before addition of acetone (0.56 mL, 7.6 mmol). It was warmed to r.t., stirred for 40 minutes and then poured into a saturated aqueous solution of ammonium chloride (6 mL). The organic <n="118"/>fraction was separated. The aqueous layer was extracted with EtOAc. The combined organic fractions were dried (MgSO4) and concentrated in vacito.' Purification by column chromatography (SiO2, gradient elution 0-50percent EtOAc in heptane) gave the title compound (713 mg, 52percent) as a clear oil. LCMS (ES+) 216, 218 (M+H)+, RT 2.75 minutes (Method 2).
48%
Stage #1: With n-butyllithium In hexane; toluene at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 1.75 h;
2-(5-Bromopyridin-2-yl)propan-2-ol
2,5-Dibromopyridine (5 g, 0.021 mol) was dissolved in toluene (100 mL).
The mixture was cooled to -78° C. A 2.5 M solution of n-butyllithium in hexane (8.44 mL, 0.021 mol) was added dropwise.
The mixture was stirred 30 minutes, followed by the addition of anhydrous acetone (10 mL).
The mixture was stirred 45 minutes and then allowed to warm to room temperature for 1 h.
The mixture was washed with aqueous ammonium chloride solution (5percent, 100 mL) and water (100 mL), then brine (100 mL).
The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (eluting with 0 to 10percent ethyl acetate in heptanes) to afford the title compound (2.21 g, 48percent) as a yellow oil. δH (500 MHz, CDCl3) 8.57 (d, J 2.1 Hz, 1H), 7.81 (dd, J 8.4, 2.3 Hz, 1H), 7.31 (d, J 8.4 Hz, 1H), 4.41 (s, 1H), 1.53 (s, 6H).

Reference: [1] Patent: US2010/41642, 2010, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2010/62571, 2010, A1, . Location in patent: Page/Page column 94-95
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5323 - 5333
[4] Tetrahedron Letters, 2000, vol. 41, # 22, p. 4335 - 4338
[5] Patent: WO2005/92899, 2005, A1, . Location in patent: Page/Page column 81
[6] Patent: EP1798229, 2007, A1, . Location in patent: Page/Page column 150
[7] Journal of Medicinal Chemistry, 2003, vol. 46, # 12, p. 2413 - 2426
[8] Patent: WO2014/81994, 2014, A1, . Location in patent: Page/Page column 73
[9] Patent: WO2009/71895, 2009, A1, . Location in patent: Page/Page column 116-117
[10] Patent: US2015/152065, 2015, A1, . Location in patent: Paragraph 0639
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1407 - 1412
[12] Patent: WO2004/814, 2003, A1, . Location in patent: Page 59
[13] Patent: US2004/102472, 2004, A1, . Location in patent: Page 33
[14] Patent: WO2004/5258, 2004, A1, . Location in patent: Page 38-39
  • 90
  • [ 624-28-2 ]
  • [ 67-64-1 ]
  • [ 477252-29-2 ]
  • [ 290307-40-3 ]
YieldReaction ConditionsOperation in experiment
34% With n-butyllithium In toluene at 0℃; EXAMPLES 8-17 The general procedures of Examples 1-4 were followed in Examples 8-17 in which 2,5 dibromopyridine was lithiated and adducts formed with different enolizable ketones. However, the batch reactions in Examples 8-17 were not run in a jacketed flask and the BuLi was added quickly via a manual syringe, instead of a syringe pump. The solution was chilled in a 0 C. ice bath prior to addition. Product distribution was determined by GC/MS (uncorrected) as described above. The percent of 2 adduct reflects the extent of lithiation at the 2 position and the percent of 5 adduct reflects the percent of lithiation at the 5 position. TABLE 3 Reac- 2-Adduct 5-Adducttion (A) (B) Ketone Type Solvent percent percent A:B Example 2-methyl- Batch toluene 75 2 47:1 ?8 3- pentanone Example 2-methyl- Flow toluene 60 8 ?8:1 ?9 3- pentanone Example 3-methyl- Batch toluene 67 2 0:1 10 2- butanone Example 3-methyl- Flow toluene 65 4 18:1 11 2- butanone Example cyclo- Batch luene 33 2 22:1 12 pentanone Example cyclo- Flow toluene 34 3 10:1 13 pentanone Example cyclo- Flow THF 0 64 100percent B 14 pentanone Example cyclo- Batch toluene 54 3 20:1 15 hexanone Example cyclo- Flow toluene 52 3 14:1 16 hexanone Example acetone Batch toluene 34 3 11:1
Reference: [1] Patent: US2006/30714, 2006, A1, . Location in patent: Page/Page column 7
  • 91
  • [ 624-28-2 ]
  • [ 290307-40-3 ]
Reference: [1] Patent: US2003/96829, 2003, A1,
[2] Patent: US2003/114478, 2003, A1,
[3] Patent: WO2015/27021, 2015, A1,
  • 92
  • [ 624-28-2 ]
  • [ 50488-42-1 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
  • 93
  • [ 624-28-2 ]
  • [ 680-15-9 ]
  • [ 436799-32-5 ]
YieldReaction ConditionsOperation in experiment
73% With copper(l) iodide In N,N-dimethyl-formamide at 100℃; for 12 h; Step 1:
Synthesis of 5-bromo-2-(trifluoromethyl)pyridine
To a stirred solution of 2,5-dibromopyridine (0.1 g, 0.421 mmol) in DMF (5.0 mL) was added Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.405 g, 2.109 mmol) along with CuI (0.401 g, 2.109 mmol) and stirred at 100° C. for 12 h.
Completion of reaction was monitored by TLC.
Reaction mass was cooled to room temperature, diluted with water, extracted with EtOAc.
Organic portions were combined, dried over Na2SO4, evaporated under reduced pressure to obtain crude product 5-bromo-2-(trifluoromethyl)pyridine (0.07 g, 73percent) as light yellow oil which was directly carry forward for next step.
MS: 227.28[M++1]
24.64%
Stage #1: With copper(l) iodide In N,N-dimethyl-formamide for 0.5 h;
Stage #2: at 20℃; for 2 h;
Step-1:
Synthesis of 5-bromo-2-(trifluoromethyl)pyridine
To a stirred solution of 2,5-dibromopyridine (0.3 g, 1.27 mmol) in DMF (10 mL), CuI (1.69 g, 8.8 mmol) was added and allow to stirred for 30 min.
To resultant reaction mass Int-A (1.22 g, 6.3 mmol) was added and stirred for 2 h at RT.
Completion of reaction was monitored by TLC. On completion, quenched with ice water, extracted with pentane.
The organic layer was washed with water, brine, dried over sodium sulphate, concentrated under reduced pressure obtained crude.
Purification of the crude was done via silica gel (100-200 Mesh) column chromatography eluent 15percent MDC/n-Hexane to obtained 5-bromo-2-(trifluoromethyl)pyridine (0.07 g, 24.64percent) as colourless oily mass.
Mass: 226.2 [M++1]
Reference: [1] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0577-0579
[2] Patent: US2017/291894, 2017, A1, . Location in patent: Paragraph 0445-0447
  • 94
  • [ 624-28-2 ]
  • [ 81290-20-2 ]
  • [ 436799-32-5 ]
Reference: [1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
  • 95
  • [ 624-28-2 ]
  • [ 436799-32-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4528 - 4532
[2] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[3] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
  • 96
  • [ 624-28-2 ]
  • [ 20857-44-7 ]
  • [ 436799-32-5 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 6, p. 1744 - 1747
  • 97
  • [ 624-28-2 ]
  • [ 5419-55-6 ]
  • [ 223463-14-7 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: With n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; for 2 h;
Stage #2: at -78℃; for 2 h;
N-{2-[4-(6-Bromo-pyridin-3-yl)-phenyl]-l-fluoromethyl-2-hydroxy-ethyl}-2,2-dichloro- acetamide (3-7) A mixture of 13 (205 mg, 0.50 mmol), 2-bromo-pyridinyl-5-boronic acid (101 mg, 0.50 mmol), K2C03 (208 mg, 1 ,50 mmol), Pd(dppf)Cl2 (28 mg, 0.025 mmol) and DMF/H20 (3: 1, 6 ml) was degassed. The mixture was heated at 80 °C for 3 h under argon atmosphere. Diluted with EtOAc (30 ml), washed with H20 (20 ml) and concentrated. The crude product was purified by PTLC (EtOAc/Hexane/MeOH, 1 :2:0.3) to afford 3-7 as a solid (80 mg, 37percent).'NMR (300 MHz, CDC13): δ 8.52 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 2.4, 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 1H), 5.87 (s, 1H), 5.20 (d, J = 3.6 Hz, 1H), 4.68 (ddd, J = 6.3, 9.3, 32.4 Hz, 1H), 4.54 (ddd, J = 4.5, 9.3, 29.4 Hz, 1H), 4.31 (m, 1H);To a solution of 2,5-dibromopyridine (2.37 g, 10 mmol) in 90 mL of Ether/THF (8: 1) was added 7.5 mL of n-BuLi (1.6 M in hexane) at -78°C dropwise. After addition, the mixture was stirred for 2h at -78°C. Triisopropylborate (4.49g, 24 mmol) was added. The resulted mixture was stirred for 2h at -78°C, then allowed to warm to rt and quenched with 10 mL of water. The reaction mixture was stirred overnight. The organic solvent was evaporated and the remaining aqueous layer was taken to pH 10 with 5percent of NaOH and washed with ether(30 mL x 3). The aqueous layer was then carefully acidified to pH 4 with 48percent of HBr to give the desired boronic acid (1.46 g, 72percent). 'NMR (300 MHz, DMSO-d3): 8.68 (dd, J = 2.1 , 0.7 Hz, 1H), 8.53 (br.s, 2H), 8.05 (dd, J = 2.1 , 7.8 Hz, 1H), 7.67 (dd, J = 7.8, 0.7 Hz, 1H).
Reference: [1] Patent: WO2012/125832, 2012, A2, . Location in patent: Page/Page column 80
  • 98
  • [ 624-28-2 ]
  • [ 223463-14-7 ]
Reference: [1] Tetrahedron, 2009, vol. 65, # 27, p. 5413 - 5417
[2] Journal of Organic Chemistry, 2002, vol. 67, # 21, p. 7541 - 7543
[3] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
  • 99
  • [ 624-28-2 ]
  • [ 163105-89-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 100
  • [ 624-28-2 ]
  • [ 76-09-5 ]
  • [ 214360-62-0 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
  • 101
  • [ 624-28-2 ]
  • [ 1195-66-0 ]
  • [ 214360-62-0 ]
Reference: [1] Chemical Science, 2014, vol. 5, # 11, p. 4317 - 4327
  • 102
  • [ 624-28-2 ]
  • [ 579525-46-5 ]
Reference: [1] Patent: WO2012/167423, 2012, A1,
[2] Patent: US2014/121200, 2014, A1,
  • 103
  • [ 624-28-2 ]
  • [ 108-95-2 ]
  • [ 59717-96-3 ]
YieldReaction ConditionsOperation in experiment
96% With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; caesium carbonate In dimethyl sulfoxide at 110℃; for 24 h; Inert atmosphere General procedure: 2,4-Dibromopyridine (0.236 g, 1 mmol) and phenol (0.094 g, 1 mmol), CuI (19.0 mg, 0.1 mmol), TMEDA (11.6 mg, 0.1 mmol), and cesium carbonate (0.65 g, 2 mmol) were placed in DMSO (5 mL). The reaction was stirred at 110 °C under nitrogen atmosphere for 24 h. When the reaction mixture was cooled, the reaction mixture was filtered. The mixture was dissolved with dichloromethane (25 mL). Then the mixture was washed with brine (3×30 mL). The organic phase was dried over sodium sulfate. After evaporation of the solvent, the mixture was subjected to column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to give pure product.
92% With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; caesium carbonate In dimethyl sulfoxide at 110℃; for 20 h; Inert atmosphere General procedure: Procedure (take intermediate 3a as an example): 2,5-dibromopyridine (61.5 mmol), phenol (64.6 mmol), cuprous iodide (6.15 mmol), and Cs2CO3 (92 mmol) were placed in a 250 mL dried flask. Add 150 mL DMSO, then add TMEDA (6.15 mmol), heated to 110 degrees under Ar protection (Unless otherwise specified, the temperature in the present invention is in degrees Celsius °C), react for about 20 hours, TLC conversion complete. After cooling to room temperature, a large amount of ethyl acetate was added, the mixture was washed 4 times with water and extracted twice with ethyl acetate. The combined EA (ethyl acetate) phase was washed with brine, and the organic layer was dried, filtered and evaporated to dryness to give the product as a brown oil.
84.4% With copper(l) iodide; copper; caesium carbonate In 1-methyl-pyrrolidin-2-one at 135℃; for 5 h; Inert atmosphere A mixture of 2,5-dibromopyridine (237mg, 1 mmol ,1.0 eq), phenol (140mg, 1.5 mmol ,1.5eq), Cu (32.5 mg, 0.5 mmol ,0.5eq), CuT (95 mg , 0.5 mmol ,0.5eq) and Cs2CO3 (978 mg, 3.0 mmol, 3.Oeq) in NMP (10 mL) was heated to 135 °C for 5 h under N2. The solid was filtered off and the filtrate was concentrated and purified by column chromatography(EA/PE=10/1, vlv) to provide 5-bromo-2- phenoxypyridine as a brown solid (200 mg, 84.4percent).
82% With sodium carbonate In N,N-dimethyl-formamide at 105℃; for 24 h; Large scale In a 100-liter reactor,Phenol (0.94 kg, 10 mol) was added successively,Dimethylformamide (20 kg),2,5-dibromopyridine (2.37 kg, 10 mol)Anhydrous sodium carbonate (1.27 kg, 12 mol),The reaction mixture was heated to 105 ° C by jacket and the reaction was stirred for 24 hours.To be 2,5-dibromopyridine consumption is complete,The reaction was cooled to room temperature, discharged, and filtered.The filtrate is returned to the reactionKettle and cooled to 0 ° C by jacket,Stirring was added in portions (40 kg)Control the temperature of 5-8 , 0.5 hours plus finished,Precipitation of light yellow solid,The mixture was stirred at this temperature for 2 hours, discharged, and filtered.The filter cake was washed with ice water (10 kg) and then filtered to dryness,The filter cake was dissolved in n-heptane (10 kg)The insoluble matter was removed by suction filtration, and the resulting filtrate was concentrated to dryness, and dimethylformamide (8 kg) was added to dissolve,The solution was cooled to 0 ° C and crushed ice (10 kg) was added over a period of 1 hour at a temperature of 3-5 ° C,Precipitation of solid, stirring 2 hours aging, suction filtration,The filter cake was washed with ice water (10 kg)Drain dry yellow solid 2.05kg,Yield: 82percent, purity: 95.4percent.
81%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333 h;
Stage #2: at 0 - 120℃; for 3.66667 h;
Manufacturing Example 40-1-1 5-Bromo-2-phenoxy-pyridine; To a solution of phenol (1.97 g, 20.9 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (1.00 g, 20.9 mmol) at 0° C., which was stirred for 5 minutes at 0° C. 2,5-Dibromopyridine (4.50 g, 19.0 mmol) was then added to this reaction solution at 0° C., and stirred for 40 minutes at room temperature. The reaction solution was then stirred for further 3 hours at 120° C. After allowing to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (3.85 g, 81percent).1H-NMR Spectrum (DMSO-d6) δ (ppm): 7.02 (1H, dd, J=0.55, 8.8 Hz), 7.11-7.14 (2H, m), 7.19-7.23 (1H, m), 7.38-7.43 (2H, m), 8.04 (1H, dd, J=2.6, 8.8 Hz), 8.25 (1H, dd, J=0.55, 2.6 Hz).
81%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333 h;
Stage #2: at 0 - 120℃; for 3.66667 h;
To a solution of phenol (1.97 g, 20.9 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (1.00 g, 20.9 mmol) at 0° C., which was stirred for 5 minutes at 0° C. 2,5-Dibromopyridine (4.50 g, 19.0 mmol) was then added to this reaction solution at 0° C., and stirred for 40 minutes at room temperature. The reaction solution was then stirred for further 3 hours at 120° C. After allowing to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (3.85 g, 81percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 7.02 (1H, dd, J=0.55, 8.8 Hz), 7.11-7.14 (2H, m), 7.19-7.23 (1H, m), 7.38-7.43 (2H, m), 8.04 (1H, dd, J=2.6, 8.8 Hz), 8.25 (1H, dd, J=0.55, 2.6 Hz).
72%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1 h; Inert atmosphere
Stage #2: at 20℃;
To a suspension of NaH (203 mg, 5.06 mmol) in DMF (15 mL), at 0 °C and under N2 atmosphere, was added phenol (437 mg, 4.64 mmol). The resulting mixture was stirred at r.t. for 1 hr before the introduction of 2,5-dibromopyridine (1 g, 4.22 mmol). Stirring was continued at r.t. overnight. After completion of the reaction, the mixture was quenched with sat. NH4CI and extracted with EA (20 mL x 4). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 20percent EA in PE) to provide 5-bromo-2-phenoxypyridine (45) (758 mg, 72 percent) as an oil. LC-MS (ESI): mlz (M/M+2) 250.1/252.1.

Reference: [1] Tetrahedron, 2013, vol. 69, # 1, p. 327 - 333
[2] Patent: CN108069974, 2018, A, . Location in patent: Paragraph 0162-0165
[3] Patent: WO2018/35061, 2018, A1, . Location in patent: Paragraph 0358
[4] Journal of Organometallic Chemistry, 2003, vol. 677, # 1-2, p. 57 - 72
[5] Patent: CN106146518, 2016, A, . Location in patent: Paragraph 0038; 0039; 0040; 0041; 0042; 0043
[6] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 87-88
[7] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 86
[8] Patent: WO2015/2894, 2015, A1, . Location in patent: Paragraph 00458
  • 104
  • [ 624-28-2 ]
  • [ 231291-22-8 ]
Reference: [1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[2] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[3] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
  • 105
  • [ 624-28-2 ]
  • [ 57260-71-6 ]
  • [ 153747-97-8 ]
YieldReaction ConditionsOperation in experiment
82% With tris-(dibenzylideneacetone)dipalladium(0); [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; sodium t-butanolate In toluene at 80℃; for 4 h; Sealed tube; Inert atmosphere To a stirred solution of 2,5-dibromopyridine (2 g, 10.7 mmol), sodium tert-butoxide (1.6 g,16.6 mmol), xantphos (400 mg, 0.7 mmol) and toluene (100 mL) in sealed tube argon waspurged for 5 min. To the reaction mixture tert-butyl piperazine-1-carboxylate (3 .4 g, 14.30mmol) followed by Pd2(dba)3 (200 mg, 0.21 mmol) was added and heated at 80 °C for 4 h(TLC indicated complete consumption of starting material). The reaction mixture was dilutedwith EtOAc (200 mL), water (100 mL), filtered through Celite bed and washed with EtOAc(2 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried overNa2S04 and concentrated under reduced pressure to give the crude product which waspurified by column chromatography (100-200 silica gel, 50 g, 10-20percent EtOAc-hexanes) toafford tert-butyl4-(5-bromo-2-pyridyl)piperazine-1-carboxylate (3 g, 82percent) as a yellow solid.LCMS (ESI+ ): m/z: 342.57 [M+Ht.
Reference: [1] Organic Letters, 2003, vol. 5, # 24, p. 4611 - 4614
[2] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 123
[3] Patent: WO2007/20888, 2007, A1, . Location in patent: Page/Page column 45-46
[4] Patent: US2006/293310, 2006, A1, . Location in patent: Page/Page column 5
  • 106
  • [ 624-28-2 ]
  • [ 227939-01-7 ]
Reference: [1] Patent: CN104292242, 2017, B,
  • 107
  • [ 624-28-2 ]
  • [ 127-19-5 ]
  • [ 214701-49-2 ]
YieldReaction ConditionsOperation in experiment
100% With n-butyllithium In hexane; toluene at -40 - 20℃; for 2 h; Inert atmosphere 2,5-dibromo-pyridine (I-1-1) 8g the (33.7mmol) and toluene 337mL was stirred at -40 under a nitrogen atmosphere. After stirring for 40 minutes was added n- butyl lithium 1.6M in hexane 21.4mL a (1.02eq) in which, in addition N, N-dimethylacetamide (DMAc) 9.38mL (3.0eq), stirred It was slowly heated to 20 while. Thereafter, saturated aqueous ammonium chloride solution was added to quench the reaction, and extraction and liquid separation. The extract was purified by silica gel column chromatography,2-acetyl-5-bromopyridine to give (compound the I-1-2) of a white solid 6.74 g (100percent yield).
65%
Stage #1: With n-butyllithium In hexane; toluene at -50℃; for 0.75 h;
Stage #2: at -50 - 20℃; for 1 h;
To a solution of 2,5-dibromopyridine (5 g, 22.026 mmol) in anhydrous toluene (200 mL) at -50 °C was added n-butyllithium (13.75 mL, 22.026 mmol) (1.6M in hexane) dropwise. The resulted mixture was stirred at -50 °C temperature for 45 mi N,Ndimethylacetamide (3.61 mL, 37.44 mmol) was added dropwise at the same temperatureand then allowed to reach room temperature slowly. The reaction mixture was stirred at room temperature for 1 h and quenched with saturated ammonium chloride solution, then extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (60-120 silica gel, 1percent EtOAc/hexane) to provide the product of Step 1 (2.9 g, 65percent yield) as a white solid. LCMS retention time: 1.46 mm(Method 7).
Reference: [1] Patent: JP2016/56276, 2016, A, . Location in patent: Paragraph 0111; 0112
[2] Tetrahedron, 2008, vol. 64, # 17, p. 3794 - 3801
[3] Dalton Transactions, 2011, vol. 40, # 29, p. 7534 - 7540
[4] Journal of the American Chemical Society, 2016, vol. 138, # 38, p. 12643 - 12647
[5] Patent: WO2015/27021, 2015, A1, . Location in patent: Page/Page column 78
[6] Patent: WO2012/21467, 2012, A1, . Location in patent: Page/Page column 32
  • 108
  • [ 624-28-2 ]
  • [ 214701-49-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 22, p. 5909 - 5915
  • 109
  • [ 624-28-2 ]
  • [ 380380-64-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 22, p. 5909 - 5915
  • 110
  • [ 624-28-2 ]
  • [ 380380-64-3 ]
  • [ 380380-63-2 ]
Reference: [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1027 - 1039
[2] Patent: CN106146559, 2016, A,
  • 111
  • [ 624-28-2 ]
  • [ 137178-88-2 ]
Reference: [1] Tetrahedron, 2005, vol. 61, # 45, p. 10748 - 10756
  • 112
  • [ 624-28-2 ]
  • [ 856866-72-3 ]
Reference: [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1027 - 1039
  • 113
  • [ 624-28-2 ]
  • [ 380917-97-5 ]
Reference: [1] Synthesis, 2012, vol. 44, # 1, p. 57 - 62
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 114
  • [ 624-28-2 ]
  • [ 874959-68-9 ]
Reference: [1] Patent: US2006/235028, 2006, A1, . Location in patent: Page/Page column 27
[2] Patent: WO2014/135471, 2014, A1,
  • 115
  • [ 624-28-2 ]
  • [ 100243-39-8 ]
  • [ 946002-90-0 ]
YieldReaction ConditionsOperation in experiment
97% With sodium carbonate In <i>tert</i>-butyl alcohol at 140℃; for 3 h; To a stirred solution of 2,5-dibromopyridine (1.0 g, 4.2 mmol) in tert-butanol (5 ml) was added (S)-3-hydroxypyrrolidine (0.74 g, 8.44 mmol; Aldrich) and sodium carbonate (1.34 g, 12.70 mmol).
The mixture was heated at 140° C. for 3 hours in a reacti-vial.
After cooling to room temperature the mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 ml).
The aqueous component was separated and extracted with ethyl acetate (20 ml).
The combined organic components were dried (Na2SO4), filtered and concentrated to give a brown oil.
The crude product mixture was purified by column chromatography (eluding with 100percent DCM-->90:10:1 DCM:MeOH:NH3) to give the desired product as a white solid (1.0 g, 97percent).
1H NMR (400 MHz, CDCl3) δ ppm 2.01-2.20 (m, 3H), 3.41-3.60 (m, 4H), 4.58-4.61 (m, 1H), 6.23 (d, 1H), 7.45 (dd, 1H), 8.11 (d, 1H). LRMS m/z (APCI) 377 [MH+].
55% for 20 h; Heating / reflux A mixture of 2,5-dibromopyridine (28.6 g, 121 mmol) and (S)-3-hydroxypyrrolidine (10.0 g, 115 mmol) in dry toluene (150 mL) was stirred under reflux for 20 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dissolved with EtOAc, and the resulting mixture was washed with aq. 10percent K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were concentrated under reduced pressure. Purification of the residue by FC(CH2Cl2/MeOH 99:1-->98:2-->97:3-->96:4-->95:5-->94:6-->93:7) yielded the title compound (15.39 g, 55percent). LC-MS: tR=0.45 min; ES+: 245.11.
46%
Stage #1: Heating / reflux
Stage #2: With potassium carbonate In water; ethyl acetate
A mixture of 2,5-dibromopyridine (12.2 g, 51.5 mmol) and (S)-hydroxypyrrolidine (2.80 g, 32.1 mmol) in toluene (50 mL) was heated to reflux overnight. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dissolved with EtOAc (150 mL), and the mixture was washed with aq. 10percent K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane-->heptane/EtOAc 1:2) yielded the title compound (3.62 g, 46percent). LC-MS: tR=0.48 min; ES+: 243.15.
46% With potassium carbonate In tolueneHeating / reflux (S)-1-(5-Bromo-pyridin-2-yl)-pyrrolidin-3-ol (G1)
A mixture of 2,5-dibromopyridine (12.2 g, 51.5 mmol) and (S)-hydroxypyrrolidine (2.80 g, 32.1 mmol) in toluene (50 mL) was heated to reflux overnight.
The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure.
The residue was dissolved with EtOAc (150 mL), and the mixture was washed with aq. 10percent K2CO3.
The org.
layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure.
Purification of the residue by FC (heptane-->heptane/EtOAc 1:2) yielded the title compound (3.62 g, 46percent). LC-MS: tR=0.48 min; ES+: 243.15.
46% Heating / reflux (S)-l-(5-Bromo-pyridin-2-yl)-pyrrolidin-3-ol (Gl). A mixture of 2,5-dibromopyridine (12.2 g, 51.5 mmol) and (5)-hydroxypyrrolidine (2.80 g, 32.1 mmol) in toluene (50 mL) was heated to reflux overnight. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dissolved with EtOAc (150 mL), and the mixture was washed with aq. 10 percent K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane - > heptane/EtOAc 1 :2) yielded the title compound (3.62 g, 46percent). LC-MS: tR = 0.48 min; ES+: 243.15.

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[2] Patent: US2009/88457, 2009, A1, . Location in patent: Page/Page column 17
[3] Patent: US2009/62342, 2009, A1, . Location in patent: Page/Page column 11
[4] Patent: US2009/176823, 2009, A1, . Location in patent: Page/Page column 39
[5] Patent: WO2007/88514, 2007, A1, . Location in patent: Page/Page column 104-105
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  • 116
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  • [ 727356-19-6 ]
Reference: [1] Patent: WO2009/120789, 2009, A1,
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  • [ 624-28-2 ]
  • [ 381233-78-9 ]
Reference: [1] Synthesis, 2012, vol. 44, # 1, p. 57 - 62
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 118
  • [ 624-28-2 ]
  • [ 381248-06-2 ]
Reference: [1] Synthesis, 2012, vol. 44, # 1, p. 57 - 62
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 119
  • [ 624-28-2 ]
  • [ 635712-99-1 ]
Reference: [1] Polyhedron, 2013, vol. 52, p. 755 - 760
  • 120
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Same Skeleton Products
Historical Records

Pharmaceutical Intermediates of
[ 624-28-2 ]

Tedizolid Related Intermediates

Chemical Structure| 656-65-5

[ 656-65-5 ]

4-Bromo-3-fluoroaniline

Chemical Structure| 113826-06-5

[ 113826-06-5 ]

(2R)-(-)-Glycidyl tosylate

Chemical Structure| 97483-77-7

[ 97483-77-7 ]

5-Bromopicolinonitrile

Chemical Structure| 510729-01-8

[ 510729-01-8 ]

Benzyl (4-bromo-3-fluorophenyl)carbamate

Chemical Structure| 380380-64-3

[ 380380-64-3 ]

5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine

Perampanel Intermediates

Chemical Structure| 381248-06-2

[ 381248-06-2 ]

3-Bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one

Chemical Structure| 381233-96-1

[ 381233-96-1 ]

5-Bromo-3-iodopyridin-2-amine

Chemical Structure| 16179-97-8

[ 16179-97-8 ]

2-(Pyridin-2-yl)acetic acid hydrochloride

Chemical Structure| 381233-78-9

[ 381233-78-9 ]

[2,3'-Bipyridin]-6'(1'H)-one

Chemical Structure| 1072-97-5

[ 1072-97-5 ]

5-Bromopyridin-2-amine

Related Functional Groups of
[ 624-28-2 ]

Bromides

Chemical Structure| 3430-26-0

[ 3430-26-0 ]

2,5-Dibromo-4-methylpyridine

Similarity: 0.84

Chemical Structure| 90902-84-4

[ 90902-84-4 ]

2,5-Dibromopyridin-3-amine

Similarity: 0.81

Chemical Structure| 221241-37-8

[ 221241-37-8 ]

2,5-Dibromopyridin-4-amine

Similarity: 0.79

Chemical Structure| 39919-65-8

[ 39919-65-8 ]

2,5-Dibromo-6-methylpyridine

Similarity: 0.79

Chemical Structure| 3430-13-5

[ 3430-13-5 ]

5-Bromo-2-methylpyridine

Similarity: 0.79

Related Parent Nucleus of
[ 624-28-2 ]

Pyridines

Chemical Structure| 3430-26-0

[ 3430-26-0 ]

2,5-Dibromo-4-methylpyridine

Similarity: 0.84

Chemical Structure| 90902-84-4

[ 90902-84-4 ]

2,5-Dibromopyridin-3-amine

Similarity: 0.81

Chemical Structure| 221241-37-8

[ 221241-37-8 ]

2,5-Dibromopyridin-4-amine

Similarity: 0.79

Chemical Structure| 39919-65-8

[ 39919-65-8 ]

2,5-Dibromo-6-methylpyridine

Similarity: 0.79

Chemical Structure| 3430-13-5

[ 3430-13-5 ]

5-Bromo-2-methylpyridine

Similarity: 0.79