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Product Details of [ 626-05-1 ]

CAS No. :626-05-1 MDL No. :MFCD00006223
Formula : C5H3Br2N Boiling Point : -
Linear Structure Formula :- InChI Key :FEYDZHNIIMENOB-UHFFFAOYSA-N
M.W : 236.89 Pubchem ID :12274
Synonyms :

Calculated chemistry of [ 626-05-1 ]      Expand+

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) : -5.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.07
Log Po/w (XLOGP3) : 2.9
Log Po/w (WLOGP) : 2.61
Log Po/w (MLOGP) : 2.01
Log Po/w (SILICOS-IT) : 2.8
Consensus Log Po/w : 2.48

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.69
Solubility : 0.0483 mg/ml ; 0.000204 mol/l
Class : Soluble
Log S (Ali) : -2.83
Solubility : 0.349 mg/ml ; 0.00147 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 : 1.77

Safety of [ 626-05-1 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 UN#:2811
Hazard Statements:H300-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 626-05-1 ]

* 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 [ 626-05-1 ]
  • Downstream synthetic route of [ 626-05-1 ]

[ 626-05-1 ] Synthesis Path-Upstream   1~140

  • 1
  • [ 626-05-1 ]
  • [ 74-88-4 ]
  • [ 5315-25-3 ]
Reference: [1] Green Chemistry, 2011, vol. 13, # 5, p. 1110 - 1113
[2] Australian Journal of Chemistry, 2013, vol. 66, # 2, p. 199 - 207
  • 2
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  • [ 917-54-4 ]
  • [ 5315-25-3 ]
Reference: [1] Acta Chemica Scandinavica, 1996, vol. 50, # 4, p. 316 - 322
  • 3
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  • [ 77-78-1 ]
  • [ 5315-25-3 ]
Reference: [1] MedChemComm, 2013, vol. 4, # 3, p. 520 - 526
  • 4
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  • [ 68-12-2 ]
  • [ 74-88-4 ]
  • [ 1122-72-1 ]
Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 1, p. 101 - 104
  • 5
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  • [ 74-88-4 ]
  • [ 3430-17-9 ]
Reference: [1] Journal of Organometallic Chemistry, 1990, vol. 382, # 3, p. 319 - 332
  • 6
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  • [ 2402-78-0 ]
Reference: [1] Chemical Communications, 2012, vol. 48, # 76, p. 9468 - 9470
  • 7
  • [ 25373-69-7 ]
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 10, p. 1656 - 1657
[2] Synthesis, 1987, # 11, p. 1013 - 1015
  • 8
  • [ 694-59-7 ]
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Reference: [1] Organic Letters, 2009, vol. 11, # 2, p. 421 - 423
[2] Journal of Organic Chemistry, 2009, vol. 74, # 21, p. 8309 - 8313
  • 9
  • [ 110-86-1 ]
  • [ 109-04-6 ]
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 381,386, 949
[2] Journal of the American Chemical Society, 1943, vol. 65, p. 2233,2235
  • 10
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Reference: [1] Patent: US3974166, 1976, A,
  • 11
  • [ 109-04-6 ]
  • [ 626-05-1 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 940,949
  • 12
  • [ 39856-57-0 ]
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Reference: [1] Roczniki Chemii, 1934, vol. 14, p. 326,330[2] Chem. Zentralbl., 1935, vol. 106, # I, p. 70
  • 13
  • [ 462-08-8 ]
  • [ 626-05-1 ]
Reference: [1] Roczniki Chemii, 1934, vol. 14, p. 326,330[2] Chem. Zentralbl., 1935, vol. 106, # I, p. 70
  • 14
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  • [ 7789-60-8 ]
  • [ 7789-69-7 ]
  • [ 626-05-1 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1939, vol. 58, p. 1100,1102
  • 15
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  • [ 141-86-6 ]
  • [ 19798-81-3 ]
YieldReaction ConditionsOperation in experiment
88.9% With ammonia In water at 190℃; for 6 h; 14.1 Preparation of 6-bromo-2-aminopyridine
In a steel autoclave having a glass insert, 10.00 g of 2,6-dibromopyridine (42.2 mmol) were suspended in 50 ml of concentrated aqueous ammonia.The autoclave was closed and heated to 190° C. for 6 h in a heating mantle (pressurized to approx. 25 bar).After the cooling and decompression of the autoclave, the contents were admixed with 100 ml of ethyl acetate and the resulting phases were separated.The aqueous phase was extracted twice with 100 ml of ethyl acetate each time, the combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure.
The residue was dissolved in 250 ml of cyclohexane/ethyl acetate (1:1) to remove 2,6-diaminopyridine which had formed, filtered together with a further 250 ml of cyclohexane/ethyl acetate (1:1) through a short silica gel column (5*20 cm), and freed of solvent under reduced pressure.Sublimation of the residue at 90° C. and 10-1 mbar afforded 6.49 g (37.5 mmol, 88.9percent) of 6-bromo-2-aminopyridine as a white solid.
Reference: [1] Patent: US2004/199024, 2004, A1, . Location in patent: Page 17
[2] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 381,386, 949
[3] Chemical Communications, 2010, vol. 46, # 6, p. 925 - 927
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  • [ 19798-81-3 ]
YieldReaction ConditionsOperation in experiment
32%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: With C10H17NO In tetrahydrofuran; hexane; toluene at -78℃; for 2 h; Inert atmosphere
General procedure: To a flame-dried reaction vial was added a solution of aryl bromide (1.0 mmol, 1.0 eq.) in 2 mL anhydrous THF. A solution of n-BuLi in hexanes (1.1 mmol, 1.1 eq.) was slowly added at −78° C. and the temperature was maintained. After 30 min, a solution of oxaziridine (1.2 mmol, 1.2 eq.) in 4 mL anhydrous toluene was added at −78° C. The reaction was allowed to proceed at −78° C. for 2 h before being quenched with saturated aqueous NH4Cl.
Reference: [1] Chemistry - A European Journal, 2009, vol. 15, # 40, p. 10405 - 10422
[2] Journal of Organic Chemistry, 2009, vol. 74, # 22, p. 8595 - 8603
[3] Patent: US2018/57444, 2018, A1, . Location in patent: Paragraph 0098; 0140; 0141; 0215
[4] Angewandte Chemie - International Edition, 2005, vol. 44, # 11, p. 1640 - 1643
[5] Patent: WO2009/17954, 2009, A1, . Location in patent: Page/Page column 27
  • 17
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  • [ 98-92-0 ]
  • [ 19798-81-3 ]
  • [ 1140964-62-0 ]
Reference: [1] Tetrahedron, 2009, vol. 65, # 10, p. 1951 - 1956
[2] Tetrahedron, 2009, vol. 65, # 10, p. 1951 - 1956
  • 18
  • [ 626-05-1 ]
  • [ 53710-17-1 ]
YieldReaction ConditionsOperation in experiment
49% With hydrogen iodide; sodium iodide In water at 140℃; for 12 h; Sealed tube; High pressure A mixture of 2,6-dibromopyridine (4.83 g, 20.4 mmol), NaI (4.00 g, 26.7 mmol, 1.3 equiv.), and 57percent HI (15 mL, 0.20 mol, 9.8 equiv.) in H2O was stirred at 140 °C in a sealed tube suitable for high-pressure reactions (Note 1) for ca. 12 h (Note 2). The resulting yellow slurry was allowed to cool to rt after which the contents of the reaction vessel were poured into crushed ice (re-melted using a heat gun if necessary). Using concentrated aqueous NaOH, the pH was adjusted to neutral and the mixture was extracted with Et2O (3 x 200 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaS2O3 (50 mL), dried with Na2SO4, filtered, and concentrated in vacuum. Purification using dry column vacuum chromatography (0–10percent EtOAc / heptanes, 1percent increments, 100 mL fractions) followed by recrystallization from boiling heptanes gave 12 (3.33 g, 20.4 mmol, 49percent) as colorless thread thin needles.
35% With copper(l) iodide; dicyclohexyl-carbodiimide; sodium iodide In 1,4-dioxane for 12 h; Reflux A mixture of 2,6-dibromopyridine (20.Og, 84.427mmol), Cul (3.86g, 20.263mmol), Nal (50. 62g, 33.708mmol) and 1,2-dicyclohexylcarbodiimide (5.86 mL, 37.148 mmol) was placed in a 250 mL two-necked flask and dissolved in 1,4-dioxane. The resultant was refluxed for 12 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove the solvent. Then, the resultant was subjected to column filtration (hexane: dichloromethane = 3: 1), and the filtrate was distilled under reduced pressure. The resultant was recrystallized from a solution of dichloromethane and petroleum ether to obtain a white powder (9. 88 g, yield: 35percent).
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
[2] European Journal of Inorganic Chemistry, 2013, # 19, p. 3334 - 3347
[3] Synlett, 2002, # 2, p. 271 - 272
[4] Journal of Organic Chemistry, 1986, vol. 51, # 6, p. 953 - 954
[5] Tetrahedron, 2016, vol. 72, # 39, p. 5831 - 5842
[6] Acta Crystallographica Section C: Crystal Structure Communications, 2002, vol. 58, # 10, p. o602-o603
[7] Patent: CN103570712, 2016, B, . Location in patent: Paragraph 0044; 0045; 0047; 0048
  • 19
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  • [ 53710-17-1 ]
  • [ 234111-08-1 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
  • 20
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  • [ 68-12-2 ]
  • [ 5431-44-7 ]
  • [ 34160-40-2 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
  • 21
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  • [ 68-12-2 ]
  • [ 5431-44-7 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 20, p. 6775 - 6786
  • 22
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  • [ 1068-55-9 ]
  • [ 68-12-2 ]
  • [ 5431-44-7 ]
  • [ 34160-40-2 ]
  • [ 153646-83-4 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
  • 23
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  • [ 873383-11-0 ]
Reference: [1] Synlett, 2015, vol. 26, # 11, p. 1557 - 1562
  • 24
  • [ 626-05-1 ]
  • [ 77-78-1 ]
  • [ 873383-11-0 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1939, vol. 58, p. 1100,1102
[2] Recueil des Travaux Chimiques des Pays-Bas, 1941, vol. 60, p. 22
  • 25
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  • [ 2408-70-0 ]
Reference: [1] Chemische Berichte, 1989, vol. 122, p. 589 - 592
[2] Dyes and Pigments, 2013, vol. 96, # 3, p. 705 - 713
  • 26
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  • [ 7726-95-6 ]
  • [ 2408-70-0 ]
  • [ 101252-31-7 ]
  • [ 2402-94-0 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1958, vol. 77, p. 66,68, 71
[2] Recueil des Travaux Chimiques des Pays-Bas, 1939, vol. 58, p. 994,995, 997
  • 27
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  • [ 39771-34-1 ]
Reference: [1] Nature Chemistry, 2017, vol. 9, # 7, p. 681 - 688
[2] Tetrahedron Letters, 2011, vol. 52, # 44, p. 5728 - 5732
[3] Patent: WO2012/41476, 2012, A1,
[4] Patent: EP2441755, 2012, A1,
[5] Patent: CN104610250, 2017, B,
[6] Patent: US2012/88750, 2012, A1,
  • 28
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  • [ 329974-09-6 ]
Reference: [1] Organic Process Research and Development, 2003, vol. 7, # 1, p. 38 - 43
[2] Organic Process Research and Development, 2003, vol. 7, # 1, p. 38 - 43
[3] Organic Process Research and Development, 2003, vol. 7, # 1, p. 38 - 43
[4] Organic Process Research and Development, 2003, vol. 7, # 1, p. 38 - 43
  • 29
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  • [ 21190-87-4 ]
Reference: [1] Journal of Organic Chemistry, 1951, vol. 16, p. 1485,1491
  • 30
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  • [ 124-38-9 ]
  • [ 21190-87-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 16, p. 2117 - 2122
  • 31
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  • [ 2893-33-6 ]
YieldReaction ConditionsOperation in experiment
34% With palladium diacetate; sodium carbonate In 1-methyl-pyrrolidin-2-one at 130℃; for 9 h; Inert atmosphere; Green chemistry General procedure: Aryl bromide (6.0 mmol), K4[Fe(CN)6]·3H2O (2.4 mmol),Na2CO3 (6.0 mmol) and Pd(OAc)2 catalyst (0.2 molpercent relative tothe aryl bromide) were mixed in NMP (12 mL) in a 25‐mLflame‐dried double‐neck round‐bottom flask and heated withstirring at 130 °C under argon. The progress of the reaction wasmonitored by GC‐MS. At the end of the reaction, the mixturewas cooled to room temperature. Samples were quenched withH2O (or with sat. NH4Cl when pyridines were used as substrates),and extracted with EtOAc (25 mL × 3). The organiclayer was washed with water (15 mL × 3) and 5percent NH3·H2O (15mL × 2), and then dried over Na2SO4. Evaporation of the solventleft the crude product, which was further purified by columnchromatography over silica gel (60–120 mesh) eluting withpetroleum ether/ethyl acetate to afford the pure aryl nitrile.1,4‐Dicyanobenzene (1b, DCB). 1H NMR (CDCl3, 400 MHz): δ= 7.80 (s, 4H); 13C NMR (101 MHz, CDCl3): δ = 132.81, 117.00,116.76.
Reference: [1] Chinese Journal of Catalysis, 2017, vol. 38, # 3, p. 583 - 588
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Reference: [1] Dalton Transactions, 2014, vol. 43, # 17, p. 6513 - 6524
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Reference: [1] ChemSusChem, 2017, vol. 10, # 11, p. 2348 - 2351
  • 34
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  • [ 39856-57-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4696 - 4701
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  • [ 10034-85-2 ]
  • [ 110-86-1 ]
  • [ 13472-80-5 ]
  • [ 7153-08-4 ]
Reference: [1] Roczniki Chemii, 1938, vol. 18, p. 96,100[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 643
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  • [ 117873-72-0 ]
Reference: [1] Helvetica Chimica Acta, 1997, vol. 80, # 1, p. 86 - 96
[2] Chemische Berichte, 1989, vol. 122, p. 589 - 592
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  • [ 13472-80-5 ]
  • [ 7153-08-4 ]
Reference: [1] Roczniki Chemii, 1938, vol. 18, p. 96,100[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 643
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  • [ 98-80-6 ]
  • [ 39774-26-0 ]
YieldReaction ConditionsOperation in experiment
93% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrabutylammomium bromide; potassium carbonate In 1,4-dioxane; water at 40℃; for 1 h; Inert atmosphere 2-Bromo-6-phenylpyridine 2,6-Dibromopyridine (2 g, 8.44 mmol), phenylboronic acid (1 .03 g, 8.44 mmol), potassium carbonate (4.67 g, 33.77 mmol) and TBAB (271 mg, 0.84 mmol) were combined in a mixture of 1 ,4-dioxane (16 ml) and water (4 ml). The reaction mixture was degassed by bubbling nitrogen through for 30 min prior to the addition of PdCI2(dppf) (62 mg, 0.084 mmol). The reaction mixture was stirred at 40 °C for 1 h before being filtered through celite. The filtrate was collected and the solvent removed. The crude material was then purified by column chromatography, eluting 100percent petroleum spirits to give the title compound as a colourless solid (1 .85 g, 93percent). 1H NMR (400 MHz, DMSO) δ 8.56 (dd, J= 6.3, 2.4 Hz, 1 H), 8.36 - 8.18 (m, 2H), 8.16 - 8.00 (m, 2H), 7.61 - 7.53 (m, 2H), 7.53 - 7.45 (m, 1 H).
74% With potassium carbonate In 1,2-dimethoxyethane; water for 24 h; Inert atmosphere; Reflux A mixture of 2,6-dibromopyridine (2.36 g, 10 mmol), phenylboronic acid (1.0 eq), Pd(OAc)2 (0.05 equiv), and PPh3 (0.2 equiv) were dissolved in dimethoxyethane/2M K2CO3 aqueous solution (80 rnL, 1 :1) under nitrogen atmosphere. The mixture was heated and refluxed for 24h. After being cooled to room temperature, the reaction mixture was diluted with EtOAc, and poured into a brine solution. The organic layer was separated, washed with the water, dried, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain the pure product Ph- Py-Br in 74percent yield. 1H NMR (CDCl3): .pound. 7.41-7.51 (m, 4H), 7.60 (dd, IH), 7.70 (dd, IH), 8.00 (dd, 2H).
34% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water for 3 h; Inert atmosphere; Reflux 1L round bottom flask equipped with in-flown plugging of the condensing tube, a nitrogen inlet port, one of the and 2, 6-dibromopyridine (15. 3 g, 64. 58 mmol), phenyl boronic acid (7. 87 g, 64. 58 mmol), and potassium carbonate (17. 58 g, 129. 16 mmol) a, 228 ml of water is added and 150 ml dimethoxyethane. The mixed nitrogen bubbling directly 15 minutes. Tetrakisphenol palladium (triphenylphosgene) (0) (1. 85 g, 1. 60 mmol) is added, the reaction mixture is heated to reflux. 3 after the completion of heating the reaction time. It is cooled to room temperature, water and diluted with ethyl acetate. Separating layer, a water layer is extracted with ethyl acetate. The organic layer is dried on magnesium sulfate, filtered, the solvent is evaporated. The substance is, 2percent ethyl acetate/hydroxyhexanamide column chromatography eluted and, subsequently, to collect the product 150 °C kouguell roll is used in a vacuum purified by distillation. 5. The obtained product of 2g (34percent).
15% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; tolueneInert atmosphere; Reflux Pitching 2 L flask, 2,6-dibromo-pyridine (2,6-dibromopyridine) 5g (0.0213mol), phenylboronic acid (phenylboronic acid) in1.3g (0.0106mol) and Pd (PPh3) 4 put 0.367g (0.32mmol) for the 36 mL Toluene 700 mL EtOH, and under a nitrogen atmosphereAfter the hash Keene, by the addition of 2M K2CO3 solution 10mL and stirred under reflux. After the reaction was terminated to cool to room temperature and 20mL H2OIt was added. Drying the mixture and then extracted twice with EtOAc 50 mL extract with Na2SO4, filtered and concentrated under a reduced pressure.Purification of the resulting compound by silica gel column chromatography to give 0.38 g compound (Intermediate 8) (yield: 15percent) of a white solid was obtained.
2.7 g With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate In water; N,N-dimethyl-formamide at 80℃; Inert atmosphere To a mixture of 2,6-dibromopyridine (3.50 g, 14.8 mmol) and phenylboronic acid (1.80 g, 14.8 mmol) in N,N-dimethylformamide (20 mL) at room temperature under nitrogen, a solution of tribasic potassium phosphate (7.80 g, 36.7 mmol) in water (14 mL) and bis(triphenylphoshine)palladium(II) dichloride (518 mg, 0.74 mmol) were added.
The mixture was deoxygenated (toggle between vacuum and nitrogen gas 5 times) and heated to 80° C. overnight.
The mixture was cooled, diluted with ethyl acetate, and washed with water and brine.
The organic layer was dried, filtered and concentrated.
The residue was purified by column chromatography on silica gel, eluting with 5percent ethyl acetate in hexanes to give a mixture containing 2-bromo-6-phenylpyridine (21-1, 2.70 g) that was used without further purification.

Reference: [1] Patent: WO2015/172196, 2015, A1, . Location in patent: Paragraph 0033; 00179; 00200
[2] Patent: WO2009/111299, 2009, A2, . Location in patent: Page/Page column 23
[3] Patent: JP5832992, 2015, B2, . Location in patent: Paragraph 0139; 0140
[4] Patent: KR2015/137230, 2015, A, . Location in patent: Paragraph 0113; 0114; 0115
[5] Patent: US2004/171614, 2004, A1,
[6] Patent: US2005/85506, 2005, A1,
[7] Patent: US2011/82164, 2011, A1, . Location in patent: Page/Page column 32
[8] Dalton Transactions, 2017, vol. 46, # 10, p. 3160 - 3169
[9] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2018, vol. 73, # 11, p. 885 - 893
[10] Patent: US2018/312523, 2018, A1, . Location in patent: Paragraph 1828; 1829
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  • [ 39774-26-0 ]
  • [ 3558-69-8 ]
YieldReaction ConditionsOperation in experiment
80% With (+/-)-7-(2,3-diacetoxypropyl)theophylline; palladium diacetate; lithium carbonate In water at 120℃; for 0.166667 h; Microwave irradiation; Green chemistry General procedure: Suzuki–Miyaura couplings were performed in glass tubes suitable for microwave. Halopyridines (0.44 mmol), phenyl boronic acid (65.17 mg, 0.53 mmol), Li2CO3 (63.7 mg, 0.89 mmol), 1 mol percent of Pd(OAc)2 (1 mg, 4.45 ϰ 10-3 mol), and 2 mol percent of the corresponding ligand in 3 mL of distilled water. The mixtures were stirred and heated at 120 °C under microwave radiation during 10 min with a ramp of 1 min in a CEM Discover reactor coupled to a CEM Explorer robotic system. The resulting reaction mixture was cooled to room temperature and the mixture extracted with CH2Cl2 (3 ϰ 2 mL), the organic phase was treated with anhydrous Na2SO4 after filter over celite and analyzed by Gas Chromatography (GC–MS) on an Agilent 6890N GC with a 30.0 m DB-1MS capillary column coupled to an Agilent 5973 Inert Mass Selective detector. Additional experiments of catalysis were carried out under the same reaction conditions using different bases Na2CO3, K2CO3, Li2CO3, Cs2CO3, Rb2CO3, NaOH, KOH, Et3N, and DIPEA.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 42, p. 5841 - 5845
[2] Molecules, 2017, vol. 22, # 3,
[3] New Journal of Chemistry, 2017, vol. 41, # 12, p. 5105 - 5113
  • 40
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  • [ 591-50-4 ]
  • [ 39774-26-0 ]
Reference: [1] Patent: US5576338, 1996, A,
  • 41
  • [ 626-05-1 ]
  • [ 603-33-8 ]
  • [ 39774-26-0 ]
Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 24, p. 5214 - 5228
  • 42
  • [ 626-05-1 ]
  • [ 24388-23-6 ]
  • [ 39774-26-0 ]
Reference: [1] Synthetic Communications, 2005, vol. 35, # 14, p. 1897 - 1902
  • 43
  • [ 626-05-1 ]
  • [ 39774-26-0 ]
Reference: [1] Tetrahedron, 2003, vol. 59, # 50, p. 10043 - 10049
[2] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
  • 44
  • [ 626-05-1 ]
  • [ 67-56-1 ]
  • [ 124-38-9 ]
  • [ 5453-67-8 ]
  • [ 6636-55-1 ]
Reference: [1] Journal of Organometallic Chemistry, 1980, vol. 186, # 2, p. 147 - 153
  • 45
  • [ 626-05-1 ]
  • [ 26218-75-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 16, p. 2117 - 2122
[2] Journal of Organic Chemistry, 1951, vol. 16, p. 1485,1491
  • 46
  • [ 626-05-1 ]
  • [ 17997-47-6 ]
  • [ 10495-73-5 ]
YieldReaction ConditionsOperation in experiment
61% With tetrakis(triphenylphosphine) palladium(0) In toluene at 80℃; for 24 h; 1.5 g (6.33 mmol) of 2,6-dibromopyridine, 3.48 g (9.48 mmol) of Intermediate 139-(1), and0.15 g (0.06 mmol) of Pd(PPh3)4 were dissolved in 15 mL of toluene in a 2-necked round-bottom flask, and stirred at about 80° C. for about 24 hours. After evaporation under reduced pressure to remove the solvent, the resulting residue was dissolved in dichloromethane, followed by extraction with 6M HC1. The aqueous layer was separated and collected, and ammonia water was added thereto, followed by extraction with dichloromethane. The resulting organic layer was separated and then dried with anhydrous MgS04, followed by evaporation under reduced pressure to remove the solvent, by drying, and by separation with column chromatography (hexane: ethyl acetate=5:l by v/v) to obtain 0.9 g of Intermediate 139-(2) as white solid (Yield: 61percent).
Reference: [1] Organic Letters, 2008, vol. 10, # 6, p. 1091 - 1094
[2] Chemical Communications, 2007, # 42, p. 4401 - 4403
[3] Organometallics, 2017, vol. 36, # 9, p. 1727 - 1735
[4] Patent: KR2015/142709, 2015, A, . Location in patent: Paragraph 0473-0475
[5] Inorganic Chemistry, 2013, vol. 52, # 9, p. 5570 - 5580
[6] Canadian Journal of Chemistry, 1997, vol. 75, # 2, p. 169 - 182
[7] Patent: WO2005/100349, 2005, A2, . Location in patent: Page/Page column 51
[8] Chemistry - A European Journal, 2012, vol. 18, # 15, p. 4593 - 4606
  • 47
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YieldReaction ConditionsOperation in experiment
63% With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 0 - 20℃; for 5 h; Inert atmosphere 2,6-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. The mixture was cooled, and 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 6-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 2
<Synthesis of 3,3'-bis(2,2'-bipyridin-6-yl)-1,1':2',1'-terphenyl (compound 3)>
2,6-Dibromopyridine (19.5 g), 2-pyridylzinc bromide (150 ml), tetrahydrofuran (90 ml), tetrakis(triphenylphosphine)palladium(0) (4.33 g) were added to a nitrogen-substituted reaction vessel.
The mixture was cooled, and stirred at 0°C for 2 hours, and then at room temperature for 3 hours.
The reaction mixture was then 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 6-bromo-2,2'-bipyridine (11.1 g; yield 63percent).
53% 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 (0.06 g, 2.0 mol percent), 2,6-dibromopyridine (0.60 g, 2.5 mmol) and 5.0 mL of 4-(ethoxycarbonyl)-phenylzinc bromide (0.5 M in THF, 2.5 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 0.31 g of 3a in 50percent isolated yield as a white solid.
33% With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 25℃; Inert atmosphere To a solution of 2,6-dibromopyridine (474 mg, 2 mmol) in tetrahydrofuran (5ml) was added Pd(PPh3)4 (23 mg, 0.02 mmol) under argon, and then a solution of pyridin-2-ylzinc(II) bromide ( 0.5M in tetrahydrofuan, 4.4 ml, 2.2 mmol). The mixture was stirred at 25 °C over a weekend, and then diluted with 150 ml ethyl acetate. The solution was washed with saturated ammonium chloride (20 ml x5) and brine. The organic phase was dried over Na2S04, filtered, and the solvents were removed under vacuum. The product was purified by ISCO chromatography (10-30percent Ethyl acetate in hexanes) to afford the title compound as a white solid (154 mg, 33percent). Calculated for C10H7BrN2, 233.98/235.98; MS (ESI) (m/z) observed 235/237 (M + 1)+. 1H NMR (300 MHz, CDCh, ppm): 58.67(d, J=5.9Hz, 1H), 8.40(t, J=7.9Hz, 2H), 7.82(t, J=7.6HZ, 1H), 7.67(t, J=8.0Hz, 1H), 7.50(d, J=7.9Hz, 1H), 7.33(t, J=5.0Hz, 1H).

Reference: [1] Patent: EP2679581, 2014, A1, . Location in patent: Paragraph 0135
[2] Patent: EP2679582, 2014, A1, . Location in patent: Paragraph 0106
[3] Organic Electronics: physics, materials, applications, 2010, vol. 11, # 12, p. 1966 - 1973
[4] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 1, p. 280 - 282
[5] Dalton Transactions, 2017, vol. 46, # 19, p. 6379 - 6391
[6] Patent: WO2018/13508, 2018, A1, . Location in patent: Paragraph 0134
  • 48
  • [ 626-05-1 ]
  • [ 10495-73-5 ]
Reference: [1] Synthetic Communications, 1990, vol. 20, # 8, p. 1233 - 1239
[2] Patent: EP1683804, 2006, A2, . Location in patent: Page/Page column 23
  • 49
  • [ 626-05-1 ]
  • [ 1148-79-4 ]
  • [ 10495-73-5 ]
Reference: [1] Synlett, 2003, # 6, p. 852 - 854
  • 50
  • [ 109-04-6 ]
  • [ 626-05-1 ]
  • [ 10495-73-5 ]
Reference: [1] Chemical Communications, 2012, vol. 48, # 48, p. 5980 - 5982
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 9, p. 2467 - 2469
  • 51
  • [ 626-05-1 ]
  • [ 882521-96-2 ]
  • [ 10495-73-5 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 2, p. 363 - 367
  • 52
  • [ 626-05-1 ]
  • [ 13737-05-8 ]
  • [ 10495-73-5 ]
Reference: [1] Nucleosides, Nucleotides and Nucleic Acids, 2002, vol. 21, # 8-9, p. 547 - 560
  • 53
  • [ 626-05-1 ]
  • [ 87905-04-2 ]
  • [ 10495-73-5 ]
Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 16, p. 4382 - 4388
  • 54
  • [ 626-05-1 ]
  • [ 21948-75-4 ]
  • [ 10495-73-5 ]
Reference: [1] Tetrahedron Letters, 1990, vol. 31, # 32, p. 4625 - 4628
  • 55
  • [ 626-05-1 ]
  • [ 611168-46-8 ]
  • [ 15862-18-7 ]
  • [ 1042150-70-8 ]
  • [ 223463-10-3 ]
Reference: [1] Polish Journal of Chemistry, 2009, vol. 83, # 2, p. 245 - 262
  • 56
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  • [ 49669-22-9 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h;
Stage #2: at -78℃; for 1 h;
Stage #3: With oxygen In diethyl ether; hexane at -78 - 20℃; for 2 h;
Example 42
6,6'-dibromo-2,2'-bipyridine 52b
In a three-necked round-bottomed flask, the 2,6-dibromopyridine (42) (2.32 g, 10 mmol) is solubilized in 250 ml of diethyl ether cooled to -78° C.
The assembly is equipped with a solids-addition funnel containing copper chloride (2) (pre-dried, 2 g, 14.9 mmol).
Butyllithium (2.4M in hexane, 4.6 ml, 11 mmol) is added dropwise and the reaction medium is stirred for 2 hours at -78° C.
The copper chloride is added slowly over 30 minutes and the mixture is stirred for a further 30 minutes at -78° C.
Dry oxygen bubbling is carried out for 1 hour at -78° C. and then for 1 hour at ambient temperature.
The reaction medium is treated with 200 ml of water and 50 ml of a 1M solution of HCl, and a precipitate appears.
The solution is filtered and the resulting solid is recrystallized from THF.
The brownish solid is subsequently solubilized in THF and filtered through a Millipore filter.
The solution is concentrated under vacuum and the desired product is obtained in the form of a white powder with a yield of 79percent.
1H NMR (CDCl3) δ(ppm): 7.50 (dd, J=0.6, 8.1, 2H, Hpyridine), 7.66 (t, J=7.8, 2H, Hpyridine), 8.37 (dd, J=0.6, 8.4, 2H, Hpyridine).
13C NMR (CDCl3) δ (ppm): 119.71, 128.15, 138.86, 141.15, 155.16.
MS, m/z (I percent): 314 (M++2, 100percent), 312 (M+, 45percent), 233 (M+-Hr, 54percent), 153 (M+-2Br, 32percent).
30%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.5 h;
Stage #2: With oxygen; copper dichloride In diethyl ether at -78 - -50℃;
The 7.15 g 2,6-dibromopyridine was stirred and dissolved in100 ml diethyl ether under room temperature, followed by addition of 15 ml (2.5 mol/L) n-BuLi drop by drop under -78 °C. Afterthe mixture was stirred under -78 °C for 0.5 h, the temperatureraised naturally to 50 C by stopping cooling, and then decreasedto -78 °C by restarting cooling, followed by adding 4.12 g CuCl2into the mixture. The resulting mixture was transferred into theoxygen atmosphere for 30 min, when reaching to -50 to -60 °C.The reaction was quenched by the addition of a few drops of water,and the liquid phase of the mixture was obtained by suction filtration,dried over Na2SO4, filtered, and evaporated under reducedpressure. After purifying by column chromatography on silica gel,6,6'-dibromo-2,2'-bipyridine was obtained in 30percent yield. 1H NMRin Fig. S1 (400 MHz, CDCl3, TMS) δ 7.50 (2H), 7.65 (2H), 8.37 (2H)ppm; 13C NMR in Fig. S1 (CDCl3, 100 MHz) δ 120.17, 128.60,139.31, 141.6, 155.62 ppm.
Reference: [1] Patent: US2010/298562, 2010, A1, . Location in patent: Page/Page column 48
[2] Dalton Transactions, 2013, vol. 42, # 45, p. 16006 - 16013
[3] Heterocycles, 2005, vol. 65, # 2, p. 293 - 301
[4] Organometallics, 2012, vol. 31, # 10, p. 3825 - 3828
[5] Synthesis, 2005, # 3, p. 458 - 464
[6] Tetrahedron Letters, 2000, vol. 41, # 13, p. 2203 - 2206
[7] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 1999, vol. 54, # 4, p. 559 - 564
[8] Journal of Catalysis, 2019, p. 249 - 256
[9] Molecules, 2012, vol. 17, # 8, p. 9010 - 9022,13
[10] European Journal of Organic Chemistry, 2009, # 28, p. 4777 - 4792
[11] Synthetic Communications, 1990, vol. 20, # 8, p. 1233 - 1239
[12] Canadian Journal of Chemistry, 1991, vol. 69, # 7, p. 1117 - 1123
[13] Journal of Organic Chemistry, 1985, vol. 50, # 17, p. 3125 - 3132
[14] Bulletin of the Chemical Society of Japan, 1984, vol. 57, # 8, p. 2121 - 2126
[15] Journal of the American Chemical Society, 2000, vol. 122, # 49, p. 12174 - 12185
[16] Synthesis, 2007, # 5, p. 791 - 793
[17] Organometallics, 2013, vol. 32, # 21, p. 6541 - 6554
[18] Organometallics, 2013, vol. 32, # 21, p. 6541 - 6554
  • 57
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YieldReaction ConditionsOperation in experiment
56% With bis(bipyridine)nickel(II) bromide; sodium iodide In N,N-dimethyl-formamide at 20℃; for 3.3 h; Electrochemical reaction; Inert atmosphere General procedure: To an undivided electrochemical cell, fitted by a zinc rod as the anode and surrounded by a nickel foam as the cathode, were added DMF (50 mL), 0.1 M NaI, and 1,2-dibromoethane (2.5 mmol, 215 μL). The mixture was electrolyzed under argon at a constant current intensity of 0.2 A at room temperature for 15-20 min. Then the current was stopped, and [Ni(bpy)]Br2 complex21 (1 mmol, 375 mg), 2,6-dichloropyridine (10 mmol, 1.48 g) or 2,6-dibromopyridine (10 mmol, 2.38 g) were sequentially added. The solution was electrolyzed at 0.1 A and room temperature until the starting material was totally consumed (3.3 h).
Reference: [1] Tetrahedron, 2012, vol. 68, # 10, p. 2383 - 2390
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  • [ 110-86-1 ]
  • [ 366-18-7 ]
  • [ 49669-22-9 ]
YieldReaction ConditionsOperation in experiment
23 %Chromat. With bis(bipyridine)nickel(II) bromide; sodium iodide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere General procedure: The controlled current preparative electrolysis were carried out with a potentiostat/galvanostat equipment. Undivided cells with 20 mL compartment were used. Zn or Fe metallic rod with 8 mm diameter was used as the sacrificial anode. Ni foam (6 cm.x.3.5 cm) was used as the cathode. It could be re-used after washing with a 6 M HCl solution following by water and acetone, and dried. The same solution was used to clean the anode. A 5 mL DMF solution containing 7percent or 20percent of NiBr2*xH2O or [Ni(bpy)]Br221 and x mmol of the corresponding mixture of 2-bromomethylpyridines or 2,6-dihalopyridines (heterocouplings in Table 1, Table 2, Table 4 and Table 5), or (2.5 mmol) of 2,6-dihalopyridines (homocoupling in Table 3) was stirred or sonicated before the electrolysis, to ensure the solubilization of reagents. A pre-electrolysis was carried out with 15 mL of the electrolytic solution (DMF, 0.1 M NaI and 0.75 mmol of 1,2-dibromoethane), passing a charge of 146 C (I=150 mA). Then, the previous prepared solution of bromopicoline or bromopyridine and the catalyst in 5 mL DMF, was added to the electrolytic cell and the constant current electrolysis (I=100 mA) applied. It is important to ensure that the cell potential must not exceed 1.8 V in order to avoid the reduction of the substrate on the cathode surface. After the total consumption of the reagent (number of coulombs described in the tables), the reaction was stopped and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with several portions of a 6 M NH4OH solution. After drying over Na2SO4, the organic layer was evaporated under reduced pressure.
7 %Chromat. With bis(bipyridine)nickel(II) bromide; sodium iodide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere General procedure: The controlled current preparative electrolysis were carried out with a potentiostat/galvanostat equipment. Undivided cells with 20 mL compartment were used. Zn or Fe metallic rod with 8 mm diameter was used as the sacrificial anode. Ni foam (6 cm.x.3.5 cm) was used as the cathode. It could be re-used after washing with a 6 M HCl solution following by water and acetone, and dried. The same solution was used to clean the anode. A 5 mL DMF solution containing 7percent or 20percent of NiBr2*xH2O or [Ni(bpy)]Br221 and x mmol of the corresponding mixture of 2-bromomethylpyridines or 2,6-dihalopyridines (heterocouplings in Table 1, Table 2, Table 4 and Table 5), or (2.5 mmol) of 2,6-dihalopyridines (homocoupling in Table 3) was stirred or sonicated before the electrolysis, to ensure the solubilization of reagents. A pre-electrolysis was carried out with 15 mL of the electrolytic solution (DMF, 0.1 M NaI and 0.75 mmol of 1,2-dibromoethane), passing a charge of 146 C (I=150 mA). Then, the previous prepared solution of bromopicoline or bromopyridine and the catalyst in 5 mL DMF, was added to the electrolytic cell and the constant current electrolysis (I=100 mA) applied. It is important to ensure that the cell potential must not exceed 1.8 V in order to avoid the reduction of the substrate on the cathode surface. After the total consumption of the reagent (number of coulombs described in the tables), the reaction was stopped and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with several portions of a 6 M NH4OH solution. After drying over Na2SO4, the organic layer was evaporated under reduced pressure.
Reference: [1] Tetrahedron, 2012, vol. 68, # 10, p. 2383 - 2390
[2] Tetrahedron, 2012, vol. 68, # 10, p. 2383 - 2390
  • 59
  • [ 626-05-1 ]
  • [ 153025-65-1 ]
  • [ 49669-22-9 ]
  • [ 161584-87-8 ]
Reference: [1] Journal of Organic Chemistry, 1995, vol. 60, # 6, p. 1755 - 1762
  • 60
  • [ 626-05-1 ]
  • [ 161584-76-5 ]
  • [ 49669-22-9 ]
  • [ 161584-87-8 ]
Reference: [1] Journal of Organic Chemistry, 1995, vol. 60, # 6, p. 1755 - 1762
  • 61
  • [ 626-05-1 ]
  • [ 49669-22-9 ]
  • [ 49669-16-1 ]
Reference: [1] Synthesis, 1995, # 8, p. 939 - 940
  • 62
  • [ 626-05-1 ]
  • [ 49669-22-9 ]
  • [ 100366-66-3 ]
  • [ 49669-16-1 ]
Reference: [1] Synthesis, 1995, # 8, p. 939 - 940
  • 63
  • [ 626-05-1 ]
  • [ 140-29-4 ]
  • [ 5005-36-7 ]
  • [ 84960-28-1 ]
  • [ 112170-37-3 ]
Reference: [1] Journal of Organic Chemistry, 1983, vol. 48, # 8, p. 1180 - 1185
  • 64
  • [ 626-05-1 ]
  • [ 124-38-9 ]
  • [ 2016-99-1 ]
  • [ 55304-85-3 ]
Reference: [1] Patent: WO2012/97682, 2012, A1, . Location in patent: Page/Page column 69-70
[2] Patent: WO2012/97479, 2012, A1, . Location in patent: Page/Page column 143
  • 65
  • [ 626-05-1 ]
  • [ 26944-71-8 ]
YieldReaction ConditionsOperation in experiment
93% With hydrazine hydrate In ethanol; water at 115℃; for 18 h; Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazine hydrate (10 mL, 97.6 mmol) in water (50-60percent) was added. The mixture was heated in a sand-bath at 115° C. for 18 h. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) to afford the title compound as an off-white solid (3.05 g, 93percent).1H-NMR (400 MHz, CDCl3): .(TM).=7.33 (t, 1H), 6.83 (d, 1H), 6.67 (d, 1H), 6.00 (br-s, 1H), 3.00-3.33 (br-s, 2H).
93% With hydrazine hydrate In ethanol; water at 115℃; for 18 h; Step A Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazine hydrate (10 mL, 97.6 mmol) in water (~50-60 percent) was added. The mixture was heated in a sand-bath at ~115 °C for 18 h. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) to afford the title compound as an off-white solid (3.05 g, 93 percent). 1H-NMR (400 MHz, CDCl3): δ = 7.33 (t, 1H), 6.83 (d, 1H), 6.67 (d, 1H), 6.00 (br-s, 1H), 3.00-3.33 (br-s, 2H)
93% With hydrazine hydrate In ethanol; water at 115℃; for 18 h; Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazine hydrate (10 mL, 97.6 mmol) in water (50-60percent) was added. The mixture was heated in a sand-bath at 115° C. for 18 h. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) to afford the title compound as an off-white solid (3.05 g, 93percent).1H-NMR (400 MHz, CDCl3): δ=3.00-3.33 (br-s, 2H), 6.00 (br-s, 1H), 6.67 (d, 1H), 6.83 (d, 1H), 7.33 (t, 1H)
93% With hydrazine hydrate In ethanol; water at 115℃; for 18 h; Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazine hydrate (10 ml_, 97.6 mmol) in water (-50-60 percent) was added. The mixture was heated in a sand-bath at ~115 °C for 18 hours. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) to afford the title compound as an off-white solid (3.05 g, 93 percent). 1H-NMR (400 MHz, CDCI3): δ = 7.33 (t, 1 H), 6.83 (d, 1 H), 6.67 (d, 1 H), 6.00 (br-s, 1 H), 3.33- 3.00 (br-s, 2H)
93% With hydrazine hydrate In ethanol; water at 115℃; for 18 h; (0761) Step A (0762) Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazine hydrate (10 mL, 97.6 mmol) in water (50-60percent) was added. The mixture was heated in a sand-bath at 115° C. for 18 hours. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) to afford the title compound as an off-white solid (3.05 g, 93percent). (0763) 1H-NMR (400 MHz, CDCl3): δ=7.33 (t, 1H), 6.83 (d, 1H), 6.67 (d, 1H), 6.00 (br-s, 1H), 3.33- 3.00 (br-s, 2H).
93% With hydrazine hydrate In ethanol; water at 115℃; for 18 h; Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazinehydrate (10 mL, 97.6 mmol) in water (∼50-60 percent) was added. The mixture was heated in a sand-bath at ∼115°C for 18 hours. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate/nheptane(60/40) to afford the title compound as an off-white solid (3.05 g, 93 percent). 1H-NMR (400 MHz, CDCl3): δ = 7.33 (t, 1 H), 6.83 (d, 1 H), 6.67 (d, 1 H), 6.00 (br-s, 1 H), 3.33-3.00 (br-s, 2H)
93% With hydrazine hydrate In ethanol; water at 115℃; for 18 h; Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazine hydrate (10 mL, 97.6 mmol) in water (-50-60 percent) was added. The mixture was heated in a sand-bath at -1 15 °C for 18 hours. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) to afford the title compound as an off-white solid (3.05 g, 93 percent). (0163) H-NMR (400 MHz, CDCI3): δ = 7.33 (t, 1 H), 6.83 (d, 1 H), 6.67 (d, 1 H), 6.00 (br-s, 1 H), 3.33- 3.00 (br-s, 2H)
93% With hydrazine hydrate In ethanol; water at 115℃; for 18 h; Commercially available 2,6-dibromopyridine (4.12 g, 16.6 mmol) was suspended in ethanol (40 mL) and hydrazine hydrate (10 mL, 97.6 mmol) in water (-50-60 percent) was added. The mixture was heated in a sand-bath at -115 °C for 18 hours. The solvent was removed and the residue was purified by chromatography on silica using ethyl acetate/n-heptane (60/40) to afford the title compound as an off-white solid (3.05 g, 93 percent). (0184) H-NMR (400 MHz, CDCI3): δ = 7.33 (t, 1H), 6.83 (d, H), 6.67 (d, 1H), 6.00 (br-s, 1H), 3.33- 3.00 (br-s, 2H)
83% at 70℃; for 0.5 h; Hydrazine (27 mL, 83 mmol) was added to 2,6-dibromopyridine (20 g, 84 mmol), and the resulting suspension was heated at 70° C. for 30 min. The solution was cooled to 50° C. and diluted with H2O (150 mL). The resulting solids were stirred for 2 h. The solids were collected by filtration and washed with H2O (350 mL) to afford the title compound (13 g, 83percent) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 6.66 (t, J=7.8 Hz, 2H), 4.19 (s, 2H).
83% at 70℃; for 0.5 h; Hydrazine (27 mL, 83 mmol) was added to 2,6-dibromopyridine (20 g, 84 mmol), and the resulting suspension was heated at 70° C. for 30 min.
The solution was cooled to 50° C. and diluted with H2O (150 mL).
The resulting solids were stirred for 2 h, collected by filtration, and washed with H2O (350 mL) to provide the title compound (13 g, 83percent) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.34 (overlapping dd, J=7.8 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 6.65 (d, J=7.8 Hz, 1H), 4.19 (s, 2H).
80% With hydrazine In ethanol; water at 80℃; for 98 h; Heating / reflux A mixture of 2,6-dibromopyridine (Aldrich; 2.37g, 0.01 mol) and hydrazine hydrate (0.53 ml) in ethanol (50 ml) was heated at 800C for 2 hours. A further portion of hydrazine hydrate (2.65 ml) was added and the mixture was heated under reflux for 4 days. The reaction was evaporated to give a cream solid. This was purified by chromatography on silica (isolute 5Og) using dichloromethane-ethanol-ammonia (300:8:1 ) as eluant. Appropriate eluates were collected and evaporated to a pale cream solid. Crystallisation from ethyl acetate- cyclohexane gave the title compound as a white fluffy solid (1.5g, 80percent). LCMS (method A): Rt = 0.68 mins; MH+ 188, 190
67% With hydrazine hydrate In butan-1-ol at 120℃; for 12 h; 2,6-dibromopyridine 2a (2.37 g, 10.0 mmol), hydrazine hydrate (20.0 mmol) and 20 mL of n-butanol was stirred at 120 ° C for 12 hours. After cooling to room temperature, the volatiles were removed under reduced pressure. The solid was washed three times with water (5 mL) and ether (5 mL) and vacuum dried at 50 ° C for 2 hours to give brown solid 4a as the target product (1.25 g, 67percent yield)

Reference: [1] Patent: US2011/256064, 2011, A1, . Location in patent: Page/Page column 22
[2] Patent: EP2377860, 2011, A1, . Location in patent: Page/Page column 29
[3] Patent: US2011/280808, 2011, A1, . Location in patent: Page/Page column 54
[4] Patent: WO2015/110263, 2015, A1, . Location in patent: Page/Page column 159
[5] Patent: US2017/2005, 2017, A1, . Location in patent: Paragraph 0760; 0761; 0762; 0763
[6] Patent: EP3118202, 2017, A1, . Location in patent: Paragraph 0102-0104
[7] Patent: WO2018/15546, 2018, A1, . Location in patent: Page/Page column 28
[8] Patent: WO2018/15549, 2018, A1, . Location in patent: Page/Page column 30
[9] Patent: US2011/3793, 2011, A1, . Location in patent: Page/Page column 98-99
[10] Patent: US2012/157460, 2012, A1, . Location in patent: Page/Page column 22
[11] Patent: WO2009/68652, 2009, A1, . Location in patent: Page/Page column 25
[12] Organometallics, 2014, vol. 33, # 4, p. 974 - 982
[13] Patent: CN104672208, 2017, B, . Location in patent: Paragraph 0025; 0026; 0027
[14] Organic Letters, 2004, vol. 6, # 26, p. 4929 - 4932
[15] Patent: US4260767, 1981, A,
[16] Patent: WO2014/201127, 2014, A2, . Location in patent: Paragraph 00584
  • 66
  • [ 626-05-1 ]
  • [ 89466-18-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4696 - 4701
  • 67
  • [ 626-05-1 ]
  • [ 51362-40-4 ]
Reference: [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 31, p. 8236 - 8239[2] Angew. Chem., 2014, vol. 53, # 31, p. 8375 - 8378,4
[3] Patent: US2016/297764, 2016, A1,
  • 68
  • [ 626-05-1 ]
  • [ 83621-01-6 ]
Reference: [1] Journal of the Chemical Society. Perkin Transactions 1, 2002, vol. 2, # 1, p. 58 - 68
[2] Synlett, 2001, # 6, p. 765 - 768
[3] Patent: EP1591443, 2005, A1,
  • 69
  • [ 626-05-1 ]
  • [ 109-94-4 ]
  • [ 21190-88-5 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #2: at -78℃; for 3 h;
Stage #3: With ethanol; iodine; potassium carbonate In tetrahydrofuran; hexane at -78 - 20℃; for 14 h;
General procedure: n-BuLi (1.67 M solution in hexane, 1.32 mL, 2.2 mmol) was added dropwise into a solution of p-bromochlorobenzene (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, ethyl formate (1.6 mL, 20 mmol) was added to the mixture and the obtained mixture was stirred at -78 °C. After 3 h at the same temperature, I2 (1523 mg, 6 mmol), K2CO3 (1382 mg, 10 mmol) and EtOH (3 mL) were added at -78 °C and the mixture was stirred for 14 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3.x.20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide ethyl 4-chlorobenzoate in 77percent yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure ethyl 4-chloro-1-benzoate as a colorless oil.
Reference: [1] Tetrahedron, 2012, vol. 68, # 24, p. 4701 - 4709
  • 70
  • [ 626-05-1 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 21190-88-5 ]
Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 25, p. 4473 - 4476
[2] Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 7757 - 7763
  • 71
  • [ 626-05-1 ]
  • [ 124-38-9 ]
  • [ 2016-99-1 ]
  • [ 55304-85-3 ]
Reference: [1] Patent: WO2012/97682, 2012, A1, . Location in patent: Page/Page column 69-70
[2] Patent: WO2012/97479, 2012, A1, . Location in patent: Page/Page column 143
  • 72
  • [ 626-05-1 ]
  • [ 49669-14-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6763 - 6770
[2] Journal of Organic Chemistry, 2006, vol. 71, # 1, p. 167 - 175
[3] Synlett, 2013, vol. 24, # 19, p. 2555 - 2558
[4] Inorganic Chemistry, 2014, vol. 53, # 11, p. 5788 - 5796
  • 73
  • [ 626-05-1 ]
  • [ 54221-96-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6763 - 6770
[2] Tetrahedron, 2005, vol. 61, # 26, p. 6207 - 6217
[3] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
  • 74
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  • [ 127-19-5 ]
  • [ 49669-13-8 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78℃; for 3 h;
2,6-dibromopyridine (10.0 g, 42.2 mmol) was placed in a reaction flask. To ensure a nitrogen atmosphere in the reaction flask, the gas in the reaction flask was drawn out and the reaction flask was refilled with nitrogen gas in a rapid manner three times. To the reaction flask, 150 ml of anhydrous diethylether was added, and then 17.7 ml of an n-butyllithium solution (44.3 mmol, 2.5 M in n-hexane) was slowly added at −78° C. to obtain a mixture. In the meanwhile, the color of the mixture changed from transparent to yellowish-brown. The mixture in the reaction flask was kept at −78° C. and continuously stirred for 30 minutes. Then, N,N-dimethylacetamide (4.7 ml, 50.7 mmol) was slowly added to the mixture, and the mixture was kept at −78° C. for 3 hours for reaction. Thereafter, the temperature of the mixture was slowly raised to 20° C. At this moment, the color of the mixture in the reaction flask changed to cloudy gray. Deionized water was slowly added to the mixture to terminate the reaction in the reaction flask. The solvents in the mixture were drawn out of the reaction flask, and the residue in the reaction flask was washed several times with ethyl acetate and with a saturated sodium chloride solution to collect an organic layer, followed by dehydration of the organic layer using sodium sulfate (Na2SO4) to thereby obtain a crude product. The crude product was subjected to column chromatography (SiO2, ethyl acetate:n-hexane=1:20), followed by recrystallization in a mixed solvent having dichloromethane and n-hexane (dichloromethane:n-hexane=1:20) at 20° C., thereby obtaining white crystals (6.80 g, 81percent yield). (0046) The spectrum analysis for the white crystals is: 1H NMR (400 MHz, CDCl3): δ 7.97 (dd, J=7.0, 1.6 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.64 (dd, J=8.0, 1.2 Hz, 1H), 2.69 (s, 3H). The white crystals were confirmed to be Compound L1-1 having a chemical structure represented by
Reference: [1] Organometallics, 2016, vol. 35, # 2, p. 198 - 206
[2] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 1, p. 116 - 118
[3] Patent: US9219237, 2015, B1, . Location in patent: Page/Page column 7
[4] Journal of Organic Chemistry, 2006, vol. 71, # 1, p. 167 - 175
[5] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6763 - 6770
[6] Journal of Organic Chemistry, 1997, vol. 62, # 23, p. 8237 - 8239
[7] Tetrahedron Asymmetry, 2000, vol. 11, # 21, p. 4341 - 4357
[8] Nucleosides and Nucleotides, 1999, vol. 18, # 6-7, p. 1657 - 1658
[9] Inorganic Chemistry, 2014, vol. 53, # 11, p. 5788 - 5796
[10] Chemische Berichte, 1992, vol. 125, # 5, p. 1169 - 1190
[11] Tetrahedron Letters, 1994, vol. 35, # 43, p. 7973 - 7976
[12] Journal of Organic Chemistry, 1998, vol. 63, # 8, p. 2481 - 2487
[13] Tetrahedron Letters, 2001, vol. 42, # 4, p. 659 - 662
[14] Tetrahedron Letters, 2003, vol. 44, # 33, p. 6305 - 6307
[15] Journal of Organometallic Chemistry, 2004, vol. 689, # 8, p. 1356 - 1361
[16] Organic and Biomolecular Chemistry, 2003, vol. 1, # 11, p. 1894 - 1899
[17] Patent: WO2009/77990, 2009, A1, . Location in patent: Page/Page column 76
[18] Dalton Transactions, 2012, vol. 41, # 6, p. 1792 - 1800
[19] Synlett, 2013, vol. 24, # 19, p. 2555 - 2558
  • 75
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  • [ 124-41-4 ]
  • [ 40473-07-2 ]
YieldReaction ConditionsOperation in experiment
89% at 120℃; for 19 h; [Referential Example 20] ;2-Bromo-6-methoxypyridine; In an argon atmosphere, sodium methoxide (1.82 g) was added to 2,6-dibromopyridine (8.0 g) in toluene (120 mL), followed by stirring at 120°C for 13 hours. Subsequently, sodium methoxide (0.728 g) was added to the mixture, followed by stirring at 120°C for 6 hours. The mixture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound in an oily substance (5.64 g, 89percent).1H-NMR(400MHz,CDCl3)δ: 3.93(3H,s), 6.68(1H,d,J=8.0Hz), 7.05(1H,d,J=7.2Hz), 7.39-7.42(1H,m).
Reference: [1] Bulletin des Societes Chimiques Belges, 1986, vol. 95, # 11, p. 1009 - 1020
[2] Patent: EP1591443, 2005, A1, . Location in patent: Page/Page column 33
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 3130 - 3141
[4] Journal of the American Chemical Society, 2002, vol. 124, # 35, p. 10443 - 10450
[5] Tetrahedron, 2010, vol. 66, # 4, p. 862 - 870
[6] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[7] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 24, p. 6763 - 6770
[8] Patent: EP1375496, 2004, A1, . Location in patent: Page 36; 28
[9] Patent: US2008/207902, 2008, A1, . Location in patent: Page/Page column 63-64
  • 76
  • [ 626-05-1 ]
  • [ 67-56-1 ]
  • [ 40473-07-2 ]
YieldReaction ConditionsOperation in experiment
7 g at 15 - 25℃; for 3 h; Step A 2-bromo-6-methoxypyridine (3a)
To a solution of sodium metal (1.5 g, 62 mmol) in methanol (200 mL) stirred at room temperature for 10 min was added 2,6-dibromopyridine (10 g, 46 mmol). The resulting solution was stirred at room temperature for 3 h. The reaction mixture was quenched with dilute HCl and then extracted with dichloromethane. The combined organic layer was washed with water, brine successively, dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The resulting crude product was purified by column by eluting with 5percent ethyl acetate in petroleum ether (v/v) to afford 2-bromo-6-methoxypyridine (7 g). MM-ESI+APCI [M+H]+m/z 187.8.
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 23, p. 7816 - 7821
[2] Synlett, 2001, # 6, p. 765 - 768
[3] Journal of the Chemical Society. Perkin Transactions 1, 2002, vol. 2, # 1, p. 58 - 68
[4] Tetrahedron, 2005, vol. 61, # 26, p. 6207 - 6217
[5] Journal of the American Chemical Society, 1994, vol. 116, # 8, p. 3657 - 3658
[6] Patent: WO2015/50798, 2015, A1, . Location in patent: Page/Page column 50
  • 77
  • [ 626-05-1 ]
  • [ 40473-07-2 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
  • 78
  • [ 626-05-1 ]
  • [ 40473-07-2 ]
Reference: [1] Patent: US6599917, 2003, B1,
  • 79
  • [ 626-05-1 ]
  • [ 68-12-2 ]
  • [ 34160-40-2 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With n-butyllithium; butyl magnesium bromide In toluene at -15 - 0℃; for 3.25 - 4.5 h; Ice/MeOH bath
Stage #2: at -15 - 5℃; for 0.75 h; Ice/MeOH bath
To a 12 L flask equipped with a mechanical stirrer, addition funnel, nitrogen inlet, and thermowell was added BuLi (619 mL, 1.55 mol). To this solution was added dry toluene (750 mL). This solution was cooled to -15° C. in an ice/MeOH bath. To this solution was added BuMgCl (387 mL, 0.774 mol) over 30-45 mins so that the temperature did not exceed 0C during the addition. A fine white to gray suspension formed. This was stirred for 30 mins at -15° C. During this time 2,6-dibromopyridine (500 g, 2.11 mol) was dissolved in dry toluene (3 L) with some slight external heating. After the stir time the solution of 2,6-dibromopyridine was charged to an addition funnel and slowly added to the reaction flask at a rate that the temperature did not exceed -5° C. (ca. 1.5 h). Once the addition of the pyridine was complete the mixture was stirred for 45 mins. Then an aliquot was taken and quenched into 20percent aqueous citric acid to determine the extent of metal exchange by 1H NMR and TLC (25percent EtOAc/heptane). A second 12 L flask equipped with a mechanical stirrer, nitrogen inlet, and thermowell was charged with toluene (750 mL) and dimethylformamide (250 mL) and cooled to -15° C. in an ice/MeOH bath. The contents of the initial reaction flask were transferred via cannula to the toluene/DMF solution at a rate that the temperature did not exceed 5° C. The reaction was stirred for 45 mins and determined to be complete. The contents of the reaction flask were transferred into a separatory funnel charged with 4 L water and citric acid (1 kg). The mixture was stirred for 15 mins, layers separated. The organic layer was washed with water (4 L), then saturated NaCl solution (4 L), then dried over Na2SO4 and solvent removed under reduced pressure to yield an off white to yellow solid of intermediate 1 (355.7 g, 90percent).
81%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h;
Stage #2: at -78℃; for 0.5 h;
In a 250 mL two-necked flask, 0.101 mol of nBuLi (2.5 M hexane solution, 40.4 mL), 80 mL of THF was added, and 2,6-dibromopyridine (C1, R1=H) (24 g, 0.1) was slowly added dropwise at -78 °C. A solution of mol in 70 mL of THF was maintained at -78 ° C for 2 hours after the addition.N,N-dimethylformamide (11.6 mL, 0.15 mol) was added dropwise, and the mixture was stirred at -78 ° C for 0.5 hour.After returning to 0 ° C, the reaction was quenched by the addition of 70 mL of CH3.To the system, 200 mL of a saturated aqueous solution of NaHCO3 was added, and a white solid was precipitated, which was extracted with CH2Cl2 (200 mL×3), and the organic phase was combined and dried over anhydrous Na2SO4.FiltrationDry, silica gel column chromatography, developing solvent for PE / EtOAc = 20/1,The compound C2 (15.154 g, 81.4 mmol) was obtained as white solid.
45%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -75℃; for 1 h; Inert atmosphere
Stage #2: at -40 - 0℃; for 1 h; Inert atmosphere
88.6 ml (0.222 mol) of n-butyllithium (2.5 M in hexane) and 350 ml of THF were placed in a 2 L round-bottom flask, stirred under nitrogen atmosphere at -75 ° C and 2,6-dibromopyridine 6-dibromopyridine (50.0 g, 0.211 mol) was dissolved in THF (245 mL) and slowly added dropwise at -75 ° C for 1 hour. After 1 hour, stir for another 30 minutes and add 24.5 ml (0.317 mol) of dimethylformamide. Then, the mixture was stirred at a reaction temperature of -40 ° C for 1-1.5 hours and then stirred for 1 hour while slowly raising the temperature to 0 ° C. After the reaction was completed, the reaction mixture was cooled to room temperature, 220 mL of MeOH was added thereto, followed by layer separation with DCM and water. The organic phase was dried over anhydrous MgSO 4 and the organic layer was concentrated and purified by silica gel column chromatography to obtain a white solid compound (Intermediate (4) 17.7 g (yield: 45percent) is obtained.
45%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -75℃; for 1.5 h; Inert atmosphere
Stage #2: at -40℃;
A 2 L round-bottomed flask was charged with 88.6 ml (0.222 mol) of n-butyllithium (2.5 M in hexane)And 350 mL of THF were added thereto. The mixture was stirred under a nitrogen atmosphere at -75 ° C, and 50.0 g (0.211 mol) of 2,6-dibromopyridine was added.Was dissolved in THF (245 mL)Under -75 was added dropwise slowly for 1 hour.After 1 hour, stir for another 30 minutes and add 24.5 ml (0.317 mol) of dimethylformamide.Then, the mixture was stirred at a reaction temperature of -40 ° C for 1-1.5 hours and then stirred for 1 hour while slowly raising the temperature to 0 ° C.After the reaction was completed, the reaction mixture was cooled to room temperature,220 mL of MeOH is added and the mixture is then partitioned between DCM and water. The organic phase is dried over anhydrous MgSO4 and the organic layer is concentrated and purified by silica gel column chromatography to obtain 17.7 g (yield: 45percent) of white solid compound (intermediate 10) .
45%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -75℃; for 1.5 h; Inert atmosphere
Stage #2: at -40 - 0℃; Inert atmosphere
A 2 L round-bottom flask was charged with 88.6 ml (0.222 mol) of n-butyllithium (2.5 M in hexane) Add 350 mL of THF and add to -75 ° C The mixture was stirred in a nitrogen atmosphere Dissolve 50.0 g (0.211 mol) of 2,6-dibromopyridine in 245 mL of THF and slowly drop it at -75 ° C for 1 hour.After 1 hour, stir for another 30 minutes and add 24.5 ml (0.317 mol) of dimethylformamide.Then, the mixture was stirred at a reaction temperature of -40 ° C for 1-1.5 hours and then stirred for 1 hour while slowly raising the temperature to 0 ° C.After the reaction was completed, the reaction mixture was cooled to room temperature,220 mL of MeOH was added, followed by layer separation with DCM and water, the organic phase was dried over anhydrous MgSO4,The organic layer was concentrated and purified by silica gel column chromatography to obtain 17.7 g (yield: 45percent) of white solid compound (intermediate (4)).

Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 20, p. 6775 - 6786
[2] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
[3] Organic Letters, 2004, vol. 6, # 12, p. 1887 - 1890
[4] Dalton Transactions, 2017, vol. 46, # 18, p. 5955 - 5964
[5] Patent: US2009/82573, 2009, A1, . Location in patent: Page/Page column 15
[6] Tetrahedron Letters, 2005, vol. 46, # 40, p. 6809 - 6814
[7] RSC Advances, 2017, vol. 7, # 83, p. 52496 - 52502
[8] Patent: CN108558868, 2018, A, . Location in patent: Paragraph 0041; 0043; 0044; 0045
[9] Journal of Organic Chemistry, 2017, vol. 82, # 10, p. 5046 - 5067
[10] Chemistry Letters, 2004, vol. 33, # 10, p. 1298 - 1299
[11] Canadian Journal of Chemistry, 2005, vol. 83, # 6-7, p. 716 - 727
[12] Journal of the Chemical Society, Dalton Transactions, 2002, # 22, p. 4224 - 4235
[13] Tetrahedron, 2001, vol. 57, # 7, p. 1175 - 1182
[14] Organic Letters, 2000, vol. 2, # 24, p. 3845 - 3848
[15] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 16, p. 1858 - 1868
[16] Angewandte Chemie - International Edition, 2018, vol. 57, # 8, p. 2238 - 2243[17] Angew. Chem., 2018, vol. 130, # 8, p. 2260 - 2265,6
[18] Journal of Organometallic Chemistry, 1998, vol. 550, # 1-2, p. 29 - 57
[19] Patent: KR2017/72856, 2017, A, . Location in patent: Paragraph 0094-0098
[20] Patent: KR2017/58623, 2017, A, . Location in patent: Paragraph 0104-0107
[21] Patent: KR2017/58618, 2017, A, . Location in patent: Paragraph 0086-0089
[22] Chemistry - A European Journal, 2015, vol. 21, # 33, p. 11735 - 11744
[23] Tetrahedron Letters, 1994, vol. 35, # 43, p. 7973 - 7976
[24] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 22, p. 3737 - 3745
[25] Journal of Organometallic Chemistry, 2004, vol. 689, # 8, p. 1356 - 1361
[26] Chemistry - A European Journal, 2006, vol. 12, # 13, p. 3472 - 3483
[27] Patent: EP2017275, 2009, A1, . Location in patent: Page/Page column 167
[28] Patent: US2009/82573, 2009, A1, . Location in patent: Page/Page column 11
[29] Patent: WO2006/96881, 2006, A1, . Location in patent: Page/Page column 58-59
[30] European Journal of Inorganic Chemistry, 2011, # 8, p. 1249 - 1254
[31] Chemical Communications, 2011, vol. 47, # 21, p. 6021 - 6023
[32] Dalton Transactions, 2012, vol. 41, # 6, p. 1792 - 1800
  • 80
  • [ 626-05-1 ]
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YieldReaction ConditionsOperation in experiment
18.0 mmol, 84% With n-butyllithium; acetic acid In tetrahydrofuran; hexane; water; N,N-dimethyl-formamide Step A
Preparation of 2-Bromo-6-formylpyridine
To a stirred solution of 2.5 M n-butyllithium in hexane (8.6 mL, 21.5 mmol) under N2, cooled to -78° C., was added dropwise a solution of 2,6-dibromopyridine (5.10 g, 21.5 mmol) in dry THF (30 mL) at such a rate that the internal temperature was below -70° C.
After complete addition, the reaction mixture was stirred at -78° C. for 15 min, and then treated with anhydrous DMF (2.6 mL, 33.3 mmol).
After 15 min, the reaction mixture was treated successively with acetic acid (1.36 mL) and water (21.5 mL) and then warmed to RT.
The reaction mixture was poured into ethyl acetate (75 mL).
The phases were separated.
The aqueous phase was extracted with ethyl acetate (25 mL).
The combined organic phases were washed with brine (35 mL), dried (MgSO4), filtered and concentrated to afford 3.33 g (18.0 mmol, 84percent) of the desired product as a white solid.
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 38, p. 6697 - 6700
[2] Tetrahedron Letters, 1996, vol. 37, # 15, p. 2537 - 2540
[3] Patent: US5116981, 1992, A,
[4] Patent: EP1308450, 2003, A2,
[5] Patent: US2004/176390, 2004, A1,
  • 81
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  • [ 109-72-8 ]
  • [ 693-04-9 ]
  • [ 34160-40-2 ]
YieldReaction ConditionsOperation in experiment
95% With acetic acid In tetrahydrofuran; hexane; N,N-dimethyl-formamide; toluene WORKING EXAMPLE 1
Production of 6-bromo-2-formylpyridine
n-Butyllithium (337 mmol) in 1.52M hexane solution (222 mL) was dissolved in toluene (500 mL) cooled at -10° C., and n-butylmagnesium chloride (169 mmol) in 2.00M tetrahydrofuran solution (84.5 ml) was added dropwise below -10° C. over a period of 25 minutes.
After stirring at -10° C. for one hour, 2,6-dibromopyridine (100 g, 422 mmol) in toluene (1000 mL) was added dropwise to the mixture at an inside temperature of -10° C. to -6° C. over one hour.
The mixture was further stirred at -10° C. for 1.5 hours and then N,N-dimethylformamide (65 mL, 840 mmol) was added dropwise below -2° C. over 20 minutes.
After further stirring at 0° C. for one hour, 10percent aqueous acetic acid solution (750 mL) was added.
The mixture was stirred under ice-cooling and the organic phase was separated.
The extract was washed with saturated aqueous sodium chloride (25 mL), dried over anhydrous sodium sulfate and concentrated to give 6-bromo-2-formylpyridine (74.68 g, 98percent purity, 95percent yield) as a pale yellowish solid. 1H-NMR (270 MHz, CDCl3, δ ppm):7.71-7.80 (m, 2H), 7.93 (m, 1H), 10.01 (s, 2H).
Reference: [1] Patent: US2003/130511, 2003, A1,
  • 82
  • [ 626-05-1 ]
  • [ 34160-40-2 ]
Reference: [1] Patent: US2002/142912, 2002, A1,
  • 83
  • [ 626-05-1 ]
  • [ 108-20-3 ]
  • [ 34160-40-2 ]
Reference: [1] Patent: US6166006, 2000, A,
  • 84
  • [ 626-05-1 ]
  • [ 68-12-2 ]
  • [ 5431-44-7 ]
  • [ 34160-40-2 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
  • 85
  • [ 626-05-1 ]
  • [ 68-12-2 ]
  • [ 109-04-6 ]
  • [ 34160-40-2 ]
  • [ 55304-83-1 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 20, p. 6775 - 6786
  • 86
  • [ 626-05-1 ]
  • [ 1068-55-9 ]
  • [ 68-12-2 ]
  • [ 5431-44-7 ]
  • [ 34160-40-2 ]
  • [ 153646-83-4 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
  • 87
  • [ 626-05-1 ]
  • [ 27992-32-1 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcoholReflux
Stage #2: With hydrogenchloride In water
A mixture of 2, 6-dibromopyridine (1) (4 g, 17 mmol), potassium t-butoxide (20 g, 0.27 mol), and redistilled t-butyl alcohol (100 mL) was refluxed overnight. After cooling, the solvent was removed in vacuo, ice/water was carefully added, and the aqueous layer was extracted with chloroform (100 mL.x.2), which removed the unreacted staring material. The aqueous layer was acidified with 3 N HCl, extracted with chloroform (100 mL.x.2), washed with brine, dried over anhydrous Na2SO4 and concentrated affording pure 6-bromo-2-pyridone (2.5 g, 85percent yields) as a white solid.
62%
Stage #1: With potassium <i>tert</i>-butylate In tert-Amyl alcohol at 100℃; for 40 h; Schlenk technique; Inert atmosphere
Stage #2: at 20℃; for 24 h;
General procedure: In a dry Schlenk tube 2-bromo-6-methylpyridine (5.98 g, 35.0 mmol) was dissolved in 100 mL oft-AmylOH and KOt-Bu (39.3 g , 350.0 mmol) was added. The mixture was stirred at 100 °C for 40 h. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL of HCO2H. The solution was stirred for 24 h at rt, then the pH was set to about 6 using 3N aq. KOH solution. The extraction was performed using CHCl3 (3×) and the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was transferred to a column chromatography (8percentMeOH in DCM) to afford 1 (white solid), 2.75 g (72percent).
17% With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol for 18 h; Reflux Potassium tert-butoxide (4.74 g, 42.2 mmol) was added to a solution of 2,6- dibromopyridine (1.00 g, 4.22 mmol) in tert-Butyl alcohol (25 mL). The reactionmixture was refluxed for 18 hours, and concentrated in vacuo. A mixture of ice and water (20 mL) was added to the residue. The aqueous layer was washed with ethyl acetate (2 x 25 mL), acidified with concentrated hydrochloric acid until pH 3 and extracted with dichloromethane (2 x 30 mL). The organic layer was washed with brine (30 mL), then dried over sodium sulfate and concentrated in vacuo to provide 6-bromo-1,2-dihydropyridin-2-one (40a) (125mg, 0.72 mmol, 17percent).1H NMR (300 MHz, ODd3) 6 6.70 (dd, J = 0.5 Hz, J = 8.6 Hz, 1H), 6.83 (dd, J = 0.5 Hz, J= 7.4 Hz, 1H), 7.44 (dd, J= 7.4 Hz, J= 8.6 Hz, 1H), 12.05 (bs, 1H).
Reference: [1] Patent: US2009/318455, 2009, A1, . Location in patent: Page/Page column 82
[2] Synlett, 2015, vol. 26, # 11, p. 1557 - 1562
[3] Patent: WO2014/57103, 2014, A1, . Location in patent: Page/Page column 174
[4] Tetrahedron, 1996, vol. 52, # 35, p. 11385 - 11404
[5] Tetrahedron, 1996, vol. 52, # 35, p. 11385 - 11404
[6] Patent: EP1577288, 2005, A1, . Location in patent: Page/Page column 110
  • 88
  • [ 626-05-1 ]
  • [ 27992-32-1 ]
  • [ 949160-14-9 ]
Reference: [1] Tetrahedron, 1996, vol. 52, # 35, p. 11385 - 11404
  • 89
  • [ 626-05-1 ]
  • [ 865-47-4 ]
  • [ 27992-32-1 ]
  • [ 949160-14-9 ]
Reference: [1] Tetrahedron, 1996, vol. 52, # 35, p. 11385 - 11404
  • 90
  • [ 626-05-1 ]
  • [ 107-31-3 ]
  • [ 55304-83-1 ]
Reference: [1] Patent: WO2006/21848, 2006, A1, . Location in patent: Page/Page column 30
  • 91
  • [ 626-05-1 ]
  • [ 68-12-2 ]
  • [ 109-04-6 ]
  • [ 34160-40-2 ]
  • [ 55304-83-1 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 20, p. 6775 - 6786
  • 92
  • [ 626-05-1 ]
  • [ 67-56-1 ]
  • [ 6231-18-1 ]
Reference: [1] Patent: CN106905229, 2017, A, . Location in patent: Paragraph 0018; 0019; 0020; 0021
[2] Chemistry - A European Journal, 2012, vol. 18, # 9, p. 2498 - 2502
[3] Organic Process Research and Development, 2008, vol. 12, # 3, p. 480 - 489
  • 93
  • [ 626-05-1 ]
  • [ 6231-18-1 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
  • 94
  • [ 626-05-1 ]
  • [ 124-41-4 ]
  • [ 6231-18-1 ]
Reference: [1] Bulletin des Societes Chimiques Belges, 1986, vol. 95, # 11, p. 1009 - 1020
  • 95
  • [ 626-05-1 ]
  • [ 144100-07-2 ]
YieldReaction ConditionsOperation in experiment
78% at 80℃; for 3 h; Heating / reflux Into a 50 mL flask equipped with a reflux condenser, 500 mg of the fluorinating agent (1) synthesized in Example 1, 236 mg of 2,6-dibromopyridine and 2 g of acetonitrile were charged and the resulting mixture was stirred for 3 hours at 80°C. After cooling to room temperature, 5 g of ethyl acetate and 5 g of water were added thereto and stirred. The mixture was separated to two layers by standing. The upper layer was analyzed by gas chromatography (internal standard method) to find that the main product was 2-fluoro-6-bromopyridine. Yield: 78percent (based on 2,6-dibromopyridine). 2,6-dibromopyridine was recovered in 20percent.
Reference: [1] Patent: EP1698606, 2006, A1, . Location in patent: Page/Page column 13
  • 96
  • [ 626-05-1 ]
  • [ 144100-07-2 ]
Reference: [1] Patent: US5630962, 1997, A,
  • 97
  • [ 626-05-1 ]
  • [ 55304-80-8 ]
YieldReaction ConditionsOperation in experiment
47.9% With nitronium tetrafluoborate In acetonitrile at 80℃; Inert atmosphere Intermediate .2: Preparation of 6-(7-azabicyclo[2.2,l]heptan-7-yl)-2- (trifluoromethyl )pyridin-3 -amine. [0218] To a solution of 2,6-dibromopyridine (10.0 g, 42.6 mmol) in anhydrous CH3CN (100 mL) was slowly added NO2+BF4' (11.3 g, 85.2 mmol). The reaction mixture was heated at 80 0C under nitrogen atmosphere for 24 h. The mixture was then evaporated to dryness and purified by silica gel chromatography (0-3percent ethyl acetate in petroleum ether) to afford 2,6- dibromo-3-nitropyridine (5.7 g, 47.9 percent). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 7 = 8.4 Hz, 1 H), 7.65 (d, 7 = 8.4 Hz, I H).
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 9, p. 3006 - 3009
[2] Patent: WO2010/48564, 2010, A1, . Location in patent: Page/Page column 49-50
[3] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4696 - 4701
  • 98
  • [ 626-05-1 ]
  • [ 5140-72-7 ]
Reference: [1] Dalton Transactions, 2015, vol. 44, # 36, p. 15905 - 15913
[2] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
[3] Tetrahedron, 2003, vol. 59, # 50, p. 10043 - 10049
  • 99
  • [ 626-05-1 ]
  • [ 5140-72-7 ]
  • [ 912934-77-1 ]
Reference: [1] Synlett, 2011, # 8, p. 1117 - 1120
  • 100
  • [ 626-05-1 ]
  • [ 68-12-2 ]
  • [ 128071-75-0 ]
Reference: [1] Journal of Organometallic Chemistry, 1990, vol. 382, # 3, p. 319 - 332
  • 101
  • [ 626-05-1 ]
  • [ 39890-95-4 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
  • 102
  • [ 626-05-1 ]
  • [ 5188-07-8 ]
  • [ 74134-42-2 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 8, p. 1839 - 1845
[2] Bulletin des Societes Chimiques Belges, 1986, vol. 95, # 11, p. 1009 - 1020
[3] Patent: US2006/211720, 2006, A1, . Location in patent: Page/Page column 77
[4] Patent: WO2004/814, 2003, A1, . Location in patent: Page 51
  • 103
  • [ 626-05-1 ]
  • [ 624-92-0 ]
  • [ 74134-42-2 ]
Reference: [1] Tetrahedron, 2000, vol. 56, # 10, p. 1349 - 1360
[2] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
  • 104
  • [ 626-05-1 ]
  • [ 74134-42-2 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
  • 105
  • [ 626-05-1 ]
  • [ 74-93-1 ]
  • [ 74134-42-2 ]
Reference: [1] Tetrahedron Letters, 1983, vol. 24, # 31, p. 3243 - 3246
  • 106
  • [ 626-05-1 ]
  • [ 75-18-3 ]
  • [ 58819-71-9 ]
  • [ 74134-42-2 ]
Reference: [1] Journal of Organometallic Chemistry, 1980, vol. 186, # 2, p. 147 - 153
  • 107
  • [ 626-05-1 ]
  • [ 124-40-3 ]
  • [ 112575-13-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 3130 - 3141
[2] Tetrahedron, 2010, vol. 66, # 4, p. 862 - 870
[3] Patent: US2009/253750, 2009, A1, . Location in patent: Page/Page column 9
[4] Patent: WO2015/75665, 2015, A1, . Location in patent: Page/Page column 117
  • 108
  • [ 626-05-1 ]
  • [ 68-12-2 ]
  • [ 40263-66-9 ]
  • [ 112575-13-0 ]
Reference: [1] Journal of Organic Chemistry, 1988, vol. 53, # 4, p. 786 - 790
[2] Journal of Organic Chemistry, 1988, vol. 53, # 4, p. 786 - 790
  • 109
  • [ 626-05-1 ]
  • [ 74-89-5 ]
  • [ 112575-13-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7758 - 7769
  • 110
  • [ 626-05-1 ]
  • [ 75-07-0 ]
  • [ 139163-56-7 ]
Reference: [1] Chemical Communications, 2016, vol. 52, # 74, p. 11056 - 11059
[2] Journal of the American Chemical Society, 2008, vol. 130, # 38, p. 12592 - 12593
[3] Chemische Berichte, 1992, vol. 125, # 5, p. 1169 - 1190
  • 111
  • [ 626-05-1 ]
  • [ 139163-56-7 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 8, p. 2481 - 2487
[2] Tetrahedron Letters, 1994, vol. 35, # 43, p. 7973 - 7976
[3] Tetrahedron Letters, 1994, vol. 35, # 43, p. 7973 - 7976
  • 112
  • [ 626-05-1 ]
  • [ 1692-15-5 ]
  • [ 106047-29-4 ]
YieldReaction ConditionsOperation in experiment
74% With potassium carbonate In tetrahydrofuran; water at 80℃; for 5 h; Synthesis Example 19: Synthesis of Intermediate 16 [Show Image] 3.08 g (13 mmol) of 2,5-dibromo pyridine, 1.23 g (10 mmol) of 4-pyridyl boronic acid, 0.58 g (0.5 mmol) of Pd(PPh3)4, and 5.53 g (40 mmol) of K2CO3 were dissolved in 50 ml of a mixed solution of THF/H2O (2:1), and the mixture was stirred at 80°C for 5 hours. The mixture was subjected to extraction three times with 60 mL of diethyl ether. An organic layer was collected and dried using magnesium sulfate to evaporate the solvent. The residue was recrystallized with dichloromethane and normal hexane to obtain 1.74 g (yield: 74percent) of Intermediate 16. This compound was identified using HR-MS. C10H7BrN2 Calculated value: 233.9793; Measured value: 233.9796
72% With potassium carbonate In tetrahydrofuran; water at 80℃; for 5 h; Synthesis of Intermediate 12; 6.16 g (26 mmol) of 2,5-dibromopyridine, 2.46 g (20 mmol) of 4-pyridylboronic acid, 1.16 g (1 mmol) of Pd(PPh3)4, and 11.1 g (80 mmol) of K2CO3 were dissolved in 100 mL of a THF/H2O (2:1) mixed solution and stirred at a temperature of 80°C for 5 hours. The reaction solution was extracted three times with 100 ml of diethylether. An organic layer was collected and dried using magnesium sulfate to evaporate the solvent. The residue was re-crystallized with dichloromethane and normal hexane to obtain 3.47 g (Yield: 72percent) of Intermediate 12. The generated compound was identified using HR-MS. C10H7BrN2 calc.: 233.9793; found 233.9795
43% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 90℃; General procedure: Boronic acid or ester (10.0 mmol), K2CO3 (25.0 mmol) in H2O (10 mL) and Pd(PPh3)4 (0.3 mmol) were added sequentially to a solution of aryl halide (10.0 mmol) in 1,4-dioxane (40 mL). The reaction mixture was stirred at 90 °C for 2-20 h and was then cooled to 20 °C and partitioned between EtOAc (200 mL) and H2O (100 mL). The organic phase was washed with water (3 .x. 50 mL), washed with brine (50 mL), dried and the solvent was evaporated. The residue was purified by column chromatography, eluting with an appropriate gradient of EtOAc/pet. ether, to give the Suzuki product.
25% With potassium carbonate In 1,4-dioxane; water at 105℃; for 12 h; Reflux Synthesis of Intermediate 1d; 181.16 g (764.72 mmol) of 2,6-dibromo pyridine and 132 g (955.9 mmol) of K2CO3 were dissolved in a mixed solution of 1,4-dioxane and H2O (v/v=1000 mL:500 mL). 47 g (382.36 mmol) of pyridine-4-boronic acid, 7 g (7.65 mmol) of tris(dibenzylideneacetone)di-palladium and P(o-Tolyl)3 were added thereto and the mixture was refluxed for 12 hours while heating at 105°C. After the reaction was completed, the mixture was cooled to room temperature and washed with ethyl acetate while being filtered with Cellite. The resulting product was subjected to extraction twice using ethyl acetate by adding a NaCl solution to a water layer. The resulting product was dried using MgSO4, concentrated, filtered using column chromatography (Hex:EA=1:1), and suspension-stirred in a Hexane(30mL)-Ether(10mL) solution, and then filtered to obtain 22.5 g of Intermediate 1d (Yield: 25percent). 1H NMR (300MHz, CDCl3) δ 7.52(d, 1H), 7.66(t, 1H), 7.76(d, 1H) 7.87(d, 2H), 8.73(d, 2H).

Reference: [1] Patent: EP2289877, 2011, A1, . Location in patent: Page/Page column 21
[2] Patent: EP2292601, 2011, A1, . Location in patent: Page/Page column 23
[3] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 11, p. 3347 - 3356
[4] Patent: EP2110373, 2009, A1, . Location in patent: Page/Page column 18-19
[5] Patent: US6174901, 2001, B1,
  • 113
  • [ 626-05-1 ]
  • [ 93830-58-1 ]
  • [ 106047-29-4 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4755 - 4763
  • 114
  • [ 220565-63-9 ]
  • [ 626-05-1 ]
  • [ 106047-28-3 ]
YieldReaction ConditionsOperation in experiment
40% 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 (0.06 g, 2.0 mol percent), 2,6-dibromopyridine (0.60 g, 2.5 mmol) and 5.0 mL of 4-(ethoxycarbonyl)-phenylzinc bromide (0.5 M in THF, 2.5 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 0.31 g of 3a in 50percent isolated yield as a white solid.
Reference: [1] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 1, p. 280 - 282
[2] Tetrahedron, 2010, vol. 66, # 17, p. 3135 - 3146
  • 115
  • [ 626-05-1 ]
  • [ 89878-14-8 ]
  • [ 106047-28-3 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4755 - 4763
[2] Patent: EP1533304, 2005, A1, . Location in patent: Page/Page column 22
  • 116
  • [ 626-55-1 ]
  • [ 626-05-1 ]
  • [ 106047-28-3 ]
Reference: [1] Synlett, 2002, # 6, p. 1008 - 1010
[2] Synthesis, 2009, # 22, p. 3823 - 3827
  • 117
  • [ 626-05-1 ]
  • [ 175422-04-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 7, p. 1273 - 1276
[2] European Journal of Inorganic Chemistry, 1998, # 9, p. 1205 - 1207
[3] Helvetica Chimica Acta, 1997, vol. 80, # 1, p. 86 - 96
[4] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3537 - 3540
[5] Patent: US2012/97899, 2012, A1,
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8307 - 8318
  • 118
  • [ 626-05-1 ]
  • [ 220616-68-2 ]
Reference: [1] Chemistry - A European Journal, 2006, vol. 12, # 30, p. 7839 - 7847
  • 119
  • [ 626-05-1 ]
  • [ 258506-66-0 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
[2] Dalton Transactions, 2015, vol. 44, # 36, p. 15905 - 15913
  • 120
  • [ 626-05-1 ]
  • [ 234111-08-1 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 23, p. 4339 - 4342
[2] Tetrahedron, 2000, vol. 56, # 10, p. 1349 - 1360
[3] Organic Letters, 2004, vol. 6, # 23, p. 4253 - 4256
[4] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
[5] Tetrahedron Letters, 2003, vol. 44, # 7, p. 1469 - 1472
  • 121
  • [ 626-05-1 ]
  • [ 53710-17-1 ]
  • [ 234111-08-1 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
  • 122
  • [ 626-05-1 ]
  • [ 87199-17-5 ]
  • [ 588727-65-5 ]
YieldReaction ConditionsOperation in experiment
72% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 70℃; for 12 h; Inert atmosphere 4-Formylphenylboronic acid (0.7 g, 4.64 mmol) was treated with 1 (1 g, 4.2 mmol) in THF:water (5:1) solvents mixture, Pd[PPh3]4 (0.24 g, 0.21 mmol), K2CO3 (1.72 g, 12.6 mmol) and stirred at 70 °C for 12 h. The completion of the reaction was monitored by TLC. The mixture is extracted with DCM and dried over Na2SO4. The compound was purified by column chromatography (silica gel 60–120 mesh, hexane/EtOAc) (4:1 v/v) as an eluent to afford the compound 7 as a solid [29].
Reference: [1] Journal of Photochemistry and Photobiology B: Biology, 2013, vol. 127, p. 212 - 222
[2] European Journal of Organic Chemistry, 2003, # 8, p. 1552 - 1558
  • 123
  • [ 626-05-1 ]
  • [ 912934-77-1 ]
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 21, p. 8274 - 8276
[2] Patent: WO2006/10629, 2006, A1, . Location in patent: Page/Page column 44
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 23, p. 8150 - 8157
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3795 - 3803
  • 124
  • [ 626-05-1 ]
  • [ 5140-72-7 ]
  • [ 912934-77-1 ]
Reference: [1] Synlett, 2011, # 8, p. 1117 - 1120
  • 125
  • [ 626-05-1 ]
  • [ 76-09-5 ]
  • [ 651358-83-7 ]
Reference: [1] Tetrahedron, 2003, vol. 59, # 50, p. 10043 - 10049
  • 126
  • [ 626-05-1 ]
  • [ 677-22-5 ]
  • [ 195044-14-5 ]
YieldReaction ConditionsOperation in experiment
10 g With copper(l) iodide In tetrahydrofuran at 0 - 20℃; for 1 h; Inert atmosphere 3neckflask, to introduce a nitrogen atmosphere, 2,6dibromopyridine14.24g, iodine screen copper (I) 0.61g, tetrahydrofuran (dehydration solvent commerciallyavailable) 180mL, and cooled to 0 . Thereto, was added dropwise to 70mL 1.0M tetrahydrofuran solution of tbutylmagnesium chloride was stirred at roomtemperature for 1 hour. Saturated aqueous ammonium chloride solution 100mL, 100mL ethyl acetate and the resulting crude by concentration of the resultingorganic layer was extracted by liquid separation, by adding a product ( ) was purified by silica gel column chromatography (solvent: hexane) by purifyingthe 2bromo6tbutylpyridine to give 10g.
Reference: [1] Organometallics, 2018, vol. 37, # 7, p. 1123 - 1132
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 24, p. 6277 - 6282[3] Angew. Chem., 2013, vol. 125, # 24, p. 6397 - 6402,6
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 10, p. 4528 - 4560
[5] Patent: KR2015/128789, 2015, A, . Location in patent: Paragraph 0813; 0814
  • 127
  • [ 626-05-1 ]
  • [ 195044-14-5 ]
YieldReaction ConditionsOperation in experiment
44% With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol 2,6-Dibromopyridine (50 g) was added to a solution of potassium tert-butoxide (35.5 g) in tert-butanol (300 ml).
The mixture was heated to reflux for 3.5 hours then cooled and concentrated.
The residue was quenched with water and extracted into ethyl acetate.
The combined organic extracts were washed with brine, dried and concentrated to give 2-bromo-6-tert-butylpyridine (21.4 g, 44percent yield) as a clear oil; 1H NMR (270 MHz): δ 1.55(9H,s), 6.58(1H,d), 6.98(1H,d), 7.33(1H,t)ppm.
Reference: [1] Patent: US6169101, 2001, A,
  • 128
  • [ 626-05-1 ]
  • [ 594-19-4 ]
  • [ 195044-14-5 ]
Reference: [1] New Journal of Chemistry, 2008, vol. 32, # 12, p. 2150 - 2158
[2] Chemistry - An Asian Journal, 2013, vol. 8, # 9, p. 2033 - 2045
  • 129
  • [ 626-05-1 ]
  • [ 122918-25-6 ]
Reference: [1] Green Chemistry, 2011, vol. 13, # 4, p. 983 - 990
  • 130
  • [ 626-05-1 ]
  • [ 67-64-1 ]
  • [ 638218-78-7 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -76 - -60℃;
Stage #2: at 20℃; Cooling with dry ice
Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water
Place a 1.6 M solution of n-butyl lithium in hexane (31.2 niL, 50 mmol) in a dry 250 rnL round bottomed flask fitted with a stir bar, septum and temperature probe. Cool in a dry- ice acetone bath to -76 0C. Add THF (30 mL) to the solution, then add a solution of 2,6- dibromopyridine (11.5 g, 50 mmol) in THF (60 mL) slowly via syringe maintaining the temperature under -600C. Stir the dark yellow-brown solution for 30 minutes in the dry- ice bath, then add acetone (6 mL, 80 mmol). Stir the deep green solution in the dry-ice bath for 15 minutes then allow the reaction to warm to room temperature. After an hour add a 5percent aqueous solution of ammonium chloride (50 mL) carefully. Extract with dichloromethane, evaporate to give 2-(6-bromo-pyridin-2-yl)-propan-2-ol (10.6 g, 98percent) as an orange oil. MS (m/z): 216 and 218 (M+H) +.
94.3% With n-butyllithium In tetrahydrofuran; hexane at -76 - 20℃; for 1.25 h; Cooling with ice Step 1
2-(6-Bromopyridin-2-yl)propan-2-ol
A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n-buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry-ice acetone bath to -76° C. and added THF (30 mL) to the solution, then added a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min.
The dark yellow-brown solution was stirred for 30 minutes in the dry-ice bath, then added propan-2-one (4.75 g, 6 mL, 81.7 mmol).
The deep green solution was stirred in the dry-ice bath for 15 minutes and then allowed to warm to room temperature.
After an hour, added carefully a saturated aqueous solution of ammonium chloride (100 mL) and product extracted with dichloromethane (3*200), combined organics dried over magnesium sulfate and evaporated.
The residue was purified by flash chromatography (silica gel 50 μm, 150 g, Analogix) eluting with 0 to 50percent over 20 min dichloromethane/hexanes, obtained 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94.3percent yield) as a light yellow clear liquid. 1H NMR (CHLOROFORM-d) δ: 7.52-7.59 (m, 1H), 7.33-7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); LC-MS 216.1, 218.1 [M+H]+.
94%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -76℃; for 0.75 h; Cooling with acetone-dry ice
Stage #2: at 20℃; for 1.25 h; Cooling with acetone-dry ice
Step 1 2-(6-Bromopyridin-2-yl)propan-2-ol A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n- buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry- ice acetone bath to -76 °C then THF (30 mL) was added followed by a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min. The dark yellow-brown solution was stirred for 30 minutes in the dry- ice bath, then propan-2-one (4.75 g, 6 mL, 81.7 mmol) was added. The deep green solution was stirred in the dry- ice bath for 15 minutes then was warmed to room temperature over 1 hour. A saturated aqueous solution of ammonium chloride (100 mL) was carefully added and the mixture extracted with dichloromethane (3 x 200 mL). The combined organic extracts were dried over magnesium sulfate then concentrated in vacuo and purified by chromatography (silica gel 50 μιη, 150g, Analogix, eluting with 0 to 50percent dichloromethane in hexanes) to obtain 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94 percent) as a light yellow, clear liquid. 1H NMR (CHLOROFORM-d) δ: 7.52 - 7.59 (m, 1H), 7.33 - 7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); MS (EI/CI) m/z: 216.1, 218.1 [M + H].
Reference: [1] Patent: WO2009/131814, 2009, A2, . Location in patent: Page/Page column 40
[2] Patent: US2013/178478, 2013, A1, . Location in patent: Paragraph 0461; 0462
[3] Patent: WO2014/60371, 2014, A1, . Location in patent: Page/Page column 76
[4] Chemical Communications, 2016, vol. 52, # 74, p. 11056 - 11059
[5] Patent: WO2004/814, 2003, A1, . Location in patent: Page 50
[6] Patent: WO2014/99695, 2014, A1, . Location in patent: Page/Page column 41
[7] Patent: WO2014/99694, 2014, A1, . Location in patent: Page/Page column 67
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  • [ 638218-78-7 ]
Reference: [1] Patent: US2003/114478, 2003, A1,
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  • [ 73874-95-0 ]
  • [ 848500-12-9 ]
YieldReaction ConditionsOperation in experiment
32% at 130 - 160℃; for 9.5 h; A mixture of 2,6-dibromo-pyridine (3.5 g, 14.77 mmol) and piperidin-4-yl-carbamic acid te/f-butyl ester (1.478 g, 7.38 mmol) is heated to 130 0C in a sealed vessel for 6.5 h and 160 0C for 3 h. The residue is cooled and dissolved in CH2CI2 , washed with saturated NaHCO3 (X2), brine, dried (Na2SO4), filtered and concentrated. The residue is then separated via flash chromatography (SiO2, 10-30percent EtOAc/hexanes gradient) to give an intermediate, (6'-bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-carbamic acid te/f-butyl ester (0.83 g, 32percent). MS (ESI) m/z 356.0, 358.0 (M+1 ), which is taken on to next step.
Reference: [1] Patent: WO2009/150230, 2009, A1, . Location in patent: Page/Page column 179
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  • [ 856013-04-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3795 - 3803
  • 134
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  • [ 358751-77-6 ]
Reference: [1] Organic Letters, 2018, vol. 20, # 1, p. 80 - 83
  • 135
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  • [ 1068-55-9 ]
  • [ 1037223-35-0 ]
Reference: [1] Chemistry - An Asian Journal, 2013, vol. 8, # 9, p. 2033 - 2045
  • 136
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  • [ 909720-21-4 ]
Reference: [1] Patent: US2008/207902, 2008, A1,
  • 137
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  • [ 885275-59-2 ]
  • [ 1044733-65-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 12, p. 3656 - 3660
  • 138
  • [ 626-05-1 ]
  • [ 1160184-14-4 ]
Reference: [1] European Journal of Organic Chemistry, 2009, # 11, p. 1781 - 1795
  • 139
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  • [ 1032582-80-1 ]
  • [ 1160184-14-4 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
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  • [ 1032582-80-1 ]
  • [ 1160184-14-4 ]
  • [ 1353056-35-5 ]
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Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
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