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Chemical Structure| 4926-28-7
Chemical Structure| 4926-28-7
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Product Details of [ 4926-28-7 ]

CAS No. :4926-28-7 MDL No. :MFCD00082590
Formula : C6H6BrN Boiling Point : -
Linear Structure Formula :- InChI Key :LSZMVESSGLHDJE-UHFFFAOYSA-N
M.W :172.02 Pubchem ID :2734087
Synonyms :

Calculated chemistry of [ 4926-28-7 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 36.9
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) : -5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.92
Log Po/w (XLOGP3) : 1.93
Log Po/w (WLOGP) : 2.15
Log Po/w (MLOGP) : 1.58
Log Po/w (SILICOS-IT) : 2.54
Consensus Log Po/w : 2.02

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.68
Solubility : 0.362 mg/ml ; 0.0021 mol/l
Class : Soluble
Log S (Ali) : -1.82
Solubility : 2.58 mg/ml ; 0.015 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.26
Solubility : 0.0948 mg/ml ; 0.000551 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.65

Safety of [ 4926-28-7 ]

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

Application In Synthesis of [ 4926-28-7 ]

* 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 [ 4926-28-7 ]
  • Downstream synthetic route of [ 4926-28-7 ]

[ 4926-28-7 ] Synthesis Path-Upstream   1~30

  • 1
  • [ 4926-28-7 ]
  • [ 461-87-0 ]
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 37, p. 5257 - 5259
  • 2
  • [ 695-34-1 ]
  • [ 4926-28-7 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With hydrogen bromide; bromine In water at -20 - -15℃; for 3 h;
Stage #2: With sodium nitrite In water at 20℃; for 3 h;
Stage #3: With sodium hydroxide In water at 0℃;
To a solution of 2-amino-4-methylpyridine (120 g, 1.1 mol) in 48percent HBr (1.5 L) at -20° C. was added bromine (160 mL, 3.11 mol) dropwise. The reaction mixture was stirred for 3 h at -15° C. to -20° C. To the above mixture was added portionwise an aqueous solution of NaNO2 (204 g, 2.95 mol). The reaction mixture was then allowed to warm to RT over a period of 3 h. A 20percent aqueous NaOH (1.2 Kg of NaOH in 2 L water) solution was added and the pH was adjusted to 12 maintaining the temperature at 0° C. The reaction mixture was extracted with diethyl ether (3.x.250 mL), washed with water, brine and dried. The solvent was removed and purified by fractional distillation to afford 2-bromo-4-methylpyridine (164 g, 86percent) as pale yellow liquid.
Reference: [1] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
[2] Chemische Berichte, 1992, vol. 125, # 5, p. 1131 - 1140
[3] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[4] Patent: US2008/51397, 2008, A1, . Location in patent: Page/Page column 9; 24
[5] Phosphorus, Sulfur and Silicon and the Related Elements, 2002, vol. 177, # 11, p. 2579 - 2587
[6] Organic Letters, 2000, vol. 2, # 21, p. 3373 - 3376
[7] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[8] Journal of the American Chemical Society, 1949, vol. 71, p. 70,73
[9] Journal of the Chemical Society, 1949, p. 2094
[10] Bulletin des Societes Chimiques Belges, 1990, vol. 99, # 9, p. 741 - 768
[11] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2791 - 2796
[12] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 2, p. 665 - 669
[13] Journal of the American Chemical Society, 1997, vol. 119, # 15, p. 3619 - 3620
[14] Tetrahedron Letters, 2005, vol. 46, # 36, p. 6033 - 6036
[15] Patent: US5324725, 1994, A,
[16] Patent: US5854234, 1998, A,
[17] Patent: US6046211, 2000, A,
[18] Patent: US2007/37974, 2007, A1, . Location in patent: Page/Page column 23
[19] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S451 - S454
  • 3
  • [ 108-89-4 ]
  • [ 4926-28-7 ]
Reference: [1] European Journal of Organic Chemistry, 2003, # 19, p. 3855 - 3860
  • 4
  • [ 13466-41-6 ]
  • [ 75-25-2 ]
  • [ 4926-28-7 ]
Reference: [1] Patent: US6005112, 1999, A,
  • 5
  • [ 108-89-4 ]
  • [ 78948-09-1 ]
  • [ 4926-28-7 ]
  • [ 108168-80-5 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6298 - 6301
  • 6
  • [ 695-34-1 ]
  • [ 4926-28-7 ]
  • [ 83004-14-2 ]
Reference: [1] Patent: US6127390, 2000, A,
  • 7
  • [ 4926-28-7 ]
  • [ 68-12-2 ]
  • [ 53547-60-7 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 8, p. 2238 - 2243[2] Angew. Chem., 2018, vol. 130, # 8, p. 2260 - 2265,6
  • 8
  • [ 4926-28-7 ]
  • [ 127-19-5 ]
  • [ 59576-26-0 ]
YieldReaction ConditionsOperation in experiment
59%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.166667 - 0.5 h;
Stage #2: at 20℃; for 2 - 14.5 h;
[Referential Example 16] 1-(6-Methoxy-3-pyridazinyl)-5-(4-methyl-2-pyridyl)-1H-pyrazole-3-carboxylic acid; [Show Image] 1) 1-(4-methyl-2-pyridyl)ethanone; A 1.58M solution of n-butyllithium in hexane (17 ml) was added dropwise over 10 minutes to a solution of 2-bromo-4-picoline (3.0 g) in diethylether (45 ml) at -78°C, and the solution was stirred for 20 minutes. N,N-dimethyl acetamide (2.5 ml) was added dropwise to the reaction liquid, and the temperature of the reaction liquid was gradually elevated to room temperature, and the mixture was stirred for 2 hours. Water and ethyl acetate were added to the reaction liquid and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 1-(4-methyl-2-pyridyl)ethanone (1.64 g, 70percent) as an oily product. 1H-NMR (400 MHz, CDCl3)δ: 2.38 (3H, s), 2.66 (3H, s), 7.23 (1H, dd, J = 4.88, 0.86 Hz), 7.81 (1H, d, J = 0.86 Hz), 8.48 (1H, d, J = 4.88 Hz).; [Referential Example 29] 5-(4-Hydroxymethyl-2-pyridyl)-1-(6-methoxy -3-pyridyl)-1H-pyrazole-3-carboxylic acid; [Show Image] 1) 2-acetyl-4-methylpyridine; A 1.58M solution of n-butyllithium in hexane (22 ml) was added dropwise to a solution of 2-bromo-4-picoline (4 g) in diethylether (60 ml) over 5 minutes at -78°C, and the mixture was stirred for 5 minutes. N,N-dimethyl acetamide (3.3 ml) was added dropwise to the reaction liquid, and the mixture was stirred at room temperature for 14.5 hours. Water and ethyl acetate were added to the reaction liquid and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 2-acetyl-4-methylpyridine (1.86 g, 59percent) as an oily product. 1H-NMR (400 MHz, CDCl3)δ: 2.42 (3H, s), 2.72 (3H, s), 7.29 (1H, dd, J = 4.94, 0.67 Hz), 7.86 (1H, d, J = 0.67 Hz), 8.54 (1H, d, J = 4.94 Hz).
59%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.166667 h;
Stage #2: at 20℃; for 14.5 h;
1) 1-(4-Methyl-2-pyridyl)-1-ethanone Under cooling to -78°C, n-butyllithium (a 1.58 M solution in hexane, 22 mL) was added dropwise to a solution of 2-bromo-4-picoline (4.0 g) in diethyl ether (60 mL) over 5 minutes, and then the resultant mixture was stirred for 5 minutes. N, N-Dimethyl acetamide (3.3 mL) was added dropwise to the reaction solution, and the mixture was gradually warmed to room temperature, and stirred for 14.5 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 1-(4-methyl-2-pyridyl)-1-ethanone (1.86 g, 59percent) as an oily product. 1H-NMR(400MHz, CDCl3)δ: 2.42(3H, s), 2.72(3H, s), 7.29(1H, dd, J=4.94, 0.67Hz), 7.86(1H, d, J=0.67Hz), 8.54(1H, d, J=4.94Hz).
Reference: [1] Patent: EP1698626, 2006, A1, . Location in patent: Page/Page column 34; 44
[2] Patent: EP1785418, 2007, A1, . Location in patent: Page/Page column 58
[3] Journal of the American Chemical Society, 1997, vol. 119, # 24, p. 5606 - 5617
  • 9
  • [ 4926-28-7 ]
  • [ 59576-26-0 ]
Reference: [1] Bulletin des Societes Chimiques Belges, 1990, vol. 99, # 9, p. 741 - 768
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 5842
  • 10
  • [ 4926-28-7 ]
  • [ 124-41-4 ]
  • [ 100848-70-2 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2791 - 2796
  • 11
  • [ 4926-28-7 ]
  • [ 13509-13-2 ]
Reference: [1] Chemistry - A European Journal, 2016, vol. 22, # 9, p. 2930 - 2934
  • 12
  • [ 4926-28-7 ]
  • [ 26156-48-9 ]
Reference: [1] Patent: US2011/111046, 2011, A1,
[2] Patent: WO2011/58473, 2011, A1,
[3] Polyhedron, 2016, vol. 118, p. 159 - 170
  • 13
  • [ 4926-28-7 ]
  • [ 6813-38-3 ]
Reference: [1] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
  • 14
  • [ 4926-28-7 ]
  • [ 71071-46-0 ]
Reference: [1] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
  • 15
  • [ 4926-28-7 ]
  • [ 66572-56-3 ]
YieldReaction ConditionsOperation in experiment
88% at 20 - 50℃; for 2 h; To a stirred solution of 29.0 g (69 mmol) 2-bromo-4-methylpyridine in 150 mL concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate.
The reaction mixture was cooled with an ice bath so that the temperature stayed between 20-50° C.
After the addition was complete, stirring was continued at room temperature for a further 2 hours.
The reaction mixture was then poured slowly onto 2 L ice-water and the mixture stirred for 1 hour at room temperature.
The resulting crystals were collected by filtration, washed with water until the washings were colorless, and dried in vacuo to afford 30.0 g (88percent) of 2-bromoisonicotinic acid.
88% at 20℃; for 3 h; Acid Preparation 13: 2-(1H-pyrazol-3-yl)isonicotinic acid To a stirred solution of 29.0 g (69 mmol) 2-bromo-4-methylpyridine in 150 mL concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate. The reaction mixture was cooled with an ice bath so that thetemperature stayed between 20-50 °C. After the addition was complete, stirring was continued at room temperature for a further 2 hours. The reaction mixture was then poured slowly onto 2 L ice-water and the mixture stirred for 1 hour at room temperature. The resulting crystals were collected by filtration, washed with water until the washings were colorless, and dried in vacuo to afford 30.0 g (88percent) of 2-bromoisonicotinic acid.
47%
Stage #1: With potassium permanganate In pyridine; water at 95℃; for 96 h;
Stage #2: With hydrogenchloride In water
To a mixture of 2-bromo-4-picoline (300 g, 1.74 mol) in pyridine/water (1 L each) at 95° C. was added KMnO4 (200 g) dissolved in water (IL). Further, added KMnO4 (2 Kg) in portions (app. 20 mg each time) over a period of 4 days. The reaction mixture was cooled to RT and filtered off the solid MnO2. The filtrate was evaporated completely under reduce pressure and acidified with 6N HCl. The solid product obtained was filtered, washed with water and dried to give 2-bromoisonicotinic acid (166 g, 47percent).
36% With potassium permanganate In water at 110℃; for 5 h; A mixture of 2-bromo-4-methylpiridine, 1, (9.27 g, 54 mmol) in 490 mL of water, and of KMnO4 (16 g, 11 mmol) in 250 mL of water were stirred for 5 h at 110 °C. The resulting mixture was filtered and the filtrate was reduced to 1/3 and acidified with HCl until pH 3. The white precipitated obtained was filtered and dried, Yield: 36percent of 2-bromoisonicotinic acid. FT-IR (KBr) ν, 3100-2350 (stretching O-H), 1710 (str. C=O), 1597 (str. C=C), 1546 (str. C=N), 1285 (str. C-O), 667 (str. C-Br) cm-1. 1H NMR (400 MHz, DMSO-d6, ppm) δ, 8.58 (dd, J = 5.0, 0.8 Hz), 7.95 (dd, J = 1.4, 0.8 Hz), 7.84 (dd, J = 5.0, 1.4 Hz).
34%
Stage #1: for 5 h; Heating / reflux
Stage #2: With hydrogenchloride In water
Example 20; Synthesis of 2-bromoisonicotinic acid; [0119] 2-Bromo-4-methylpyridine (10 g, 0.058 moles) and potassium permanganate (18.3 g, 0.115 moles) was combined in water (500 ml). The mixture was refluxed for five hours, filtered through celite and reduced in volume to-400 ml. The dark brown solution was acidified with hydrochloric acid (10percent) to pH-3. The resulting white precipitate was filtered and rinsed with ethyl ether. 2-Bromoisonicotinic acid was isolated in 34 percent yield. 1H NMR (DMSO-d6) 7.8 (1H, d), 7.85 (1H, s), 8.5 (1H, d).
20.3% With potassium permanganate In waterReflux To 1.84 g ( 1 1.6 mmol) of KMn04 in 10 mL of H20 was added 0.65 mL (5.8 mmol) of 2-bromo-4-methylpyridine via syringe. The solution was refluxed for 1 hr, after which 1.25 equivalents ( 1.15 g; 7.25 mmol) of KMn04 was added. After an additional 2 hr reflux, 1.25 equivalents of KMn04 was added and stirred overnight to produce a dark solution containing a black suspension. After filtration through celite, the clear aqueous layer was washed with 3 x 20 mL of ethyl acetate. The aqueous layer was brought to a pH of 4 using 1M HC1 to precipitate out 237 mg of a white solid (yield = 20.3percent). ESI-MS: m/z, 199.7 (calcd for M+ 199.9) NMR (DMSO-d6): δ 7.84 (dd, 1H, J = 5 Hz, \\l = lHz), 7.96 (s, 1H), 8.59 (d, 1H, J = 5 Hz), 14.02 (vbr, 1H).
88% With potassium dichromate In sulfuric acid a
2-Bromo-Isonicotinic Acid
To a stirred solution of 29.0 g (1(69 mmol) 2-bromo-4-methylpyridine in 150 ml concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate and the reaction mixture was cooled with an ice bath so that the temperature stayed between 20-50° C.
After the addition was complete, stirring was continued at room temperature for a further 2 h.
The reaction mixture was then poured slowly onto 2 l ice-water and the mixture stirred for 1 hour at room temperature.
The resulting crystals were collected by filtration, washed with water until the washings were colourless, and dried in vacuo to afford 30.0 g (88percent) 2-bromo-isonicotinic acid as a white crystalline solid. EI-MS m/e (percent): 203 (M{81Br}+, 100), 201 (M{79Br}+, 93).

Reference: [1] Patent: US2011/111046, 2011, A1, . Location in patent: Page/Page column 17; 18
[2] Patent: WO2011/58473, 2011, A1, . Location in patent: Page/Page column 36; 37
[3] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[4] Patent: US2008/51397, 2008, A1, . Location in patent: Page/Page column 9; 24
[5] Polyhedron, 2016, vol. 118, p. 159 - 170
[6] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 2, p. 665 - 669
[7] Patent: WO2005/84439, 2005, A1, . Location in patent: Page/Page column 37
[8] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
[9] Patent: WO2011/32269, 2011, A1, . Location in patent: Page/Page column 33-34
[10] Synthesis, 2003, # 4, p. 551 - 554
[11] Patent: US2005/54654, 2005, A1, . Location in patent: Page/Page column 36
[12] Patent: US2003/134854, 2003, A1,
[13] Patent: WO2006/21801, 2006, A1, . Location in patent: Page/Page column 45
[14] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S451 - S454
  • 16
  • [ 4926-28-7 ]
  • [ 1333-82-0 ]
  • [ 66572-56-3 ]
Reference: [1] Patent: US4912101, 1990, A,
  • 17
  • [ 4926-28-7 ]
  • [ 89978-52-9 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
  • 18
  • [ 109-04-6 ]
  • [ 4926-28-7 ]
  • [ 108-89-4 ]
  • [ 366-18-7 ]
  • [ 1134-35-6 ]
  • [ 56100-19-7 ]
YieldReaction ConditionsOperation in experiment
45 %Chromat. With nickel(II) bromide hydrate; 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
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  • [ 4926-28-7 ]
  • [ 110-86-1 ]
  • [ 108-89-4 ]
  • [ 366-18-7 ]
  • [ 1134-35-6 ]
  • [ 56100-19-7 ]
YieldReaction ConditionsOperation in experiment
35 %Chromat. With nickel(II) bromide hydrate; 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
  • 20
  • [ 4926-28-7 ]
  • [ 17997-47-6 ]
  • [ 56100-19-7 ]
Reference: [1] Organic Letters, 2000, vol. 2, # 21, p. 3373 - 3376
[2] Journal of Organic Chemistry, 2002, vol. 67, # 23, p. 8269 - 8272
  • 21
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  • [ 56100-19-7 ]
Reference: [1] Synlett, 2003, # 6, p. 852 - 854
  • 22
  • [ 4926-28-7 ]
  • [ 882521-96-2 ]
  • [ 56100-19-7 ]
Reference: [1] Synthesis, 2010, # 1, p. 85 - 90
  • 23
  • [ 4926-28-7 ]
  • [ 118289-17-1 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 36, p. 6033 - 6036
[2] Tetrahedron Letters, 2001, vol. 42, # 39, p. 6815 - 6818
[3] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
  • 24
  • [ 4926-28-7 ]
  • [ 118289-16-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
  • 25
  • [ 4926-28-7 ]
  • [ 83004-14-2 ]
Reference: [1] Patent: US2004/248884, 2004, A1, . Location in patent: Page 121
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 5071 - 5074
[3] Patent: US6362336, 2002, B1, . Location in patent: Example 59
  • 26
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  • [ 34241-39-9 ]
  • [ 83004-14-2 ]
Reference: [1] Patent: US5962458, 1999, A,
  • 27
  • [ 695-34-1 ]
  • [ 4926-28-7 ]
  • [ 83004-14-2 ]
Reference: [1] Patent: US6127390, 2000, A,
  • 28
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  • [ 446880-81-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2210 - 2221
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5642 - 5645
  • 29
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  • [ 68-12-2 ]
  • [ 955370-07-7 ]
YieldReaction ConditionsOperation in experiment
76.5%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -70℃; for 0.5 h; Inert atmosphere
Stage #2: at -70℃; for 0.25 h; Inert atmosphere
To a stirred solution of n-butyllithium (1 L, 1 .6 M in hexane) in tetrahydrofuran was added diisopropylamine (600 mL) dropwise through a dropping funnel at -10 °C under an N2 atmosphere for 30 minutes. The ice bath was removed and the reaction mixture was cooled to -78 °C. A solution of 2-bromo-6-methyl pyridine (100 g, 0.58 mol) in THF ( .6 L) was added and the color changed pale yellow to dark brown. The mixture was stirred for 1 hour at the same temperature and then Λ/,Λ/'-dimethylformamide (200 mL, 2.147 mol) was added. After 60 minutes at -78 °C, methanol (1.6 L) and acetic acid (160 mL, 2.49 mol) were added. Then sodium borohydride (28 g, 0.557 mol) was added at -78 °C and the mixture was allowed to come to room temperature and was stirred overnight. The color changed dark brown to yellow color. The reaction mixture was diluted with ethyl acetate (3.0 L) and 10percent citric acid solution (1.5 L) and was extracted with EtOAc (2 x 2L), and washed with brine (1 L). The combined organic extracts were dried over Na2S04 and solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using ethyl acetate/n-heptane (30/70) to afford the title compound as a pale yellow oil (90 g, 76.5percent). 1H-NMR (400 MHz, CDCI3): δ = 7.43 (t, 1 H), 7.34 (d, 1 H), 7.16 (d, 1 H), 4.02 (q, 2H), 3.09 (t, 1 H), 3.01 (t, 2H)
Reference: [1] Patent: WO2015/110263, 2015, A1, . Location in patent: Page/Page column 199
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  • [ 4926-28-7 ]
  • [ 183483-29-6 ]
Reference: [1] Patent: US2012/184539, 2012, A1,
[2] Patent: WO2018/106636, 2018, A1,
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