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Chemical Structure| 13466-43-8
Chemical Structure| 13466-43-8
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Product Details of [ 13466-43-8 ]

CAS No. :13466-43-8 MDL No. :MFCD03411569
Formula : C5H4BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :YDUGVOUXNSWQSW-UHFFFAOYSA-N
M.W : 174.00 Pubchem ID :818549
Synonyms :

Calculated chemistry of [ 13466-43-8 ]

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 : 1.0
Molar Refractivity : 34.76
TPSA : 32.86 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.57 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.32
Log Po/w (XLOGP3) : 1.11
Log Po/w (WLOGP) : 1.14
Log Po/w (MLOGP) : 1.03
Log Po/w (SILICOS-IT) : 2.27
Consensus Log Po/w : 1.37

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.17
Solubility : 1.17 mg/ml ; 0.00671 mol/l
Class : Soluble
Log S (Ali) : -1.39
Solubility : 7.04 mg/ml ; 0.0404 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.78
Solubility : 0.289 mg/ml ; 0.00166 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.47

Safety of [ 13466-43-8 ]

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 [ 13466-43-8 ]

* 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 [ 13466-43-8 ]
  • Downstream synthetic route of [ 13466-43-8 ]

[ 13466-43-8 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 142-08-5 ]
  • [ 13466-38-1 ]
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Reference: [1] Synthesis, 2001, # 14, p. 2175 - 2179
  • 2
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  • [ 52200-48-3 ]
Reference: [1] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
  • 3
  • [ 13466-43-8 ]
  • [ 13466-35-8 ]
Reference: [1] Tetrahedron Letters, 1996, vol. 37, # 37, p. 6695 - 6698
  • 4
  • [ 13534-99-1 ]
  • [ 13466-43-8 ]
YieldReaction ConditionsOperation in experiment
90% With sulfuric acid; sodium nitrite In water at 0℃; for 1 h; Inert atmosphere At 0°C, sodium nitrite (24.2 g, 0.35 mol, 4.84 equiv.) dissolved in water (175 mL) wasadded dropwise to a solution of 2-amino-3-bromo-2-pyridine (12.5 g, 72.4 mmol) andsulfuric acid (35 mL, 0.66 mol, 9.10 equiv.) in water (175 mL). The reaction was stirred 1h and neutralized with NaOH concentrated solution. The pH=7 solution was extractedwith chloroform (3 x 200 mL), washed with brine (200 mL), dried with magnesiumsulfate, filtered and concentrated in vacuo to give a cream solid (11.3 g, 90percent). M.P. :183°C; IR (neat) νmax 3339, 3105, 2991, 2942, 1776, 1650, 1610, 1464 cm-1; 1H NMR(500 MHz, CDCl3) δ = 7.87 (dd, J = 7.3, 1.9 Hz, 1H), 7.49 (dd, J = 6.4, 1.9 Hz, 1H), 6.24 (dd,J = 7.3, 6.4 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 161.9, 143.9, 134.4, 115.7, 107.7ppm; HRMS: m/z [ESI] calcd for C5H4BrNONa (M+Na)+ : 195.9369, found : 195.9373(+2.07 ppm).
Reference: [1] Organic Letters, 2016, vol. 18, # 13, p. 3106 - 3109
[2] Synthesis (Germany), 2016, vol. 48, # 20, p. 3575 - 3588
  • 5
  • [ 142-08-5 ]
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YieldReaction ConditionsOperation in experiment
78% With bromine; potassium bromide In water at 20℃; for 24.25 h; 3-l3romo-pyridin-2-ol. A stirred suspension of 2-pyridone (77-0, 19 g, 200 mmol) in 200 mE of 1 M aqueous K13r at room temperature was treated over 15 mm with bromine (32 g, 200 mmol; CAUTION: Large quantities of 13r2 should be handled careffilly) in 200 mE of 1 M aqueous K13r, then stirred vigorously at room temperature 0/N. After 24 h, this solution deposited crystals which were filtered off and then recrystallized from acetonitrile to give 27.2 g (78percent) of 3-bromo- pyridin-2-ol. (77-1) [J. Am. Chem. Soc. 1982, 104, 4142- 4146; Bioorg. Med. Chem. Lett. 2002, 12, 197-200; JMed Chem. 1979, 22, 1284-1290.] Molecular weight calcd. for C5H4I3rNO: 173; (M+H) found: 174
Reference: [1] Patent: US2018/110824, 2018, A1, . Location in patent: Paragraph 0497; 0498; 0499
[2] Patent: US6110914, 2000, A,
  • 6
  • [ 142-08-5 ]
  • [ 13466-38-1 ]
  • [ 13466-43-8 ]
Reference: [1] Synthesis, 2001, # 14, p. 2175 - 2179
  • 7
  • [ 13472-81-6 ]
  • [ 13466-43-8 ]
Reference: [1] Synlett, 2003, # 11, p. 1678 - 1682
  • 8
  • [ 98273-62-2 ]
  • [ 13466-43-8 ]
Reference: [1] Journal of Organic Chemistry, 1958, vol. 23, p. 1616
  • 9
  • [ 13466-43-8 ]
  • [ 74-88-4 ]
  • [ 81971-38-2 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With potassium <i>tert</i>-butylate In 1,4-dioxane at 100℃; for 2 h; Schlenk technique; Inert atmosphere
Stage #2: at 80℃; for 16 h; Schlenk technique; Inert atmosphere
General procedure: In a dry Schlenk tube 6-methyl-2(1H)-pyridone (1) (3.43 g, 31.44 mmol) was dissolved in 50 mLof 1,4-dioxane and KOt-Bu (8.69 g, 62.88 mmol) was added. The mixture was stirred at 100 °C for 2 h, then cooled down to rt, MeI (19.6 mL, 314.41 mmol) was added dropwise and the mixture was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure and the residue was separated between DCM and water. The extraction was performed using DCM (3×) and the combined organic phases were dried over MgSO4, filtered and evaporated. The residue was transferred to a column chromatography (5percent MeOH in DCM) to afford 3a (orange solid), 3.70 g (96percent).
79% With potassium carbonate In 1,2-dimethoxyethane Example 19
A mixture of 3-bromo-1H-2-pyridone (740 mg, 4.25 mmol), potassium carbonate (1.18 g, 8.5 mmol) and iodomethane (2.65 mL, 42.5 mmol) in DME (10 mL) was heated to reflux overnight.
The mixture was filtered, washing with ethyl acetate and the filtrate was evaporated to dryness.
The residue was purified by dry column chromatography over 27 g of silica gel, eluding with ethyl acetate to give 3-bromo-1-methyl-2-pyridone (0.63 g, 79percent). LRMS (electrospray), positive ion, 188 (M+H).
74.7%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h;
Stage #2: for 2 h;
To a stirred solution of 3-bromopyridin-2(1H)-one (44-1) (1 g, 5.74 mmol) in dry DMF (4 mL ) at 0°C, was added NaH (343 mg, 8.61 mmol) and the mixture was stirred for 30 minutes followed by addition of iodomethane (976 mg, 6.88 mmol) and stirring for another 2 h. After completion of reaction as monitored by TLC, the mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over sodium sulfate, concentrated, and the residue was purified over silica to obtain 3-bromo-1-methylpyridin-2(1H)-one (44-2) (800 mg, 4.25 mmol, 74.7 percent) as a solid. LC MS: ES+ 188.0.
Reference: [1] Synlett, 2015, vol. 26, # 11, p. 1557 - 1562
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7076 - 7080
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 4840 - 4860
[4] Patent: US6388084, 2002, B1,
[5] Patent: WO2017/197046, 2017, A1, . Location in patent: Page/Page column 344; 345
[6] Chemical Biology and Drug Design, 2016, vol. 87, # 5, p. 694 - 703
  • 10
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  • [ 74-88-4 ]
  • [ 81971-38-2 ]
YieldReaction ConditionsOperation in experiment
92% With tetra-(n-butyl)ammonium iodide; potassium carbonate In toluene at 40℃; for 15 h; At 40° C., a mixture of 5.0 g (28.7 mmol) of 3-bromo-2-hydroxypyridine, 17.9 ml (0.287 mol) of iodomethane, 1.06 g (2.87 mmol) of tetra-n-butylammonium iodide and 19.9 g (0.144 mol) of potassium carbonate is stirred in 60 ml of toluene for 15 hours. 250 ml of water are then added, and the reaction mixture is extracted with ethyl acetate.
The organic extract is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate.
After filtration and removal of the solvent on a rotary evaporator, the product is isolated by filtration with suction through silica gel using cyclohexane/ethyl acetate 1:1-->1:3 as mobile phase.
This gives 4.97 g (92percent of theory) of the title compound.
1H-NMR (400 MHz, CDCl3, δ/ppm): 7.73 (dd, 1H), 7.30 (dd, 1H), 6.06 (dd, 1H), 3.61 (s, 3H).
GC/MS (method 10): Rt=5.62 min.
MS (ES+, m/z): 187/189 (79Br/81Br) (M)+.
86% With tetra-(n-butyl)ammonium iodide; potassium carbonate In toluene at 40℃; for 17 h; Methyl iodide (1.5 mL, 24.14 mmol) was added to a suspension of potassium carbonate (1668 mg, 12.07 mmol), TBAI (89 mg, 0.24 mmol) and 3-bromopyridin-2-ol (420 mg,2.4 14 mmol) in toluene (15 mL). The reaction mixture was heated to 40 °C for 17 hours. The mixture was partitioned between DCM and water and the combined extracts dried (hydrophobic fit) and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluted with 0-70percent petrol/ethyl acetate to afford 3 -bromo- 1- methylpyridin-2(1H)-one, Intermediate 5 (390 mg, 86 percent).‘H NMR (400 MHz, DMSO-d6) & 3.50 (s, 3 H) 6.17 (t, J=7.07 Hz, 1 H) 7.78 (dd, J=6.82,1.77 Hz, 1 H) 7.90 (dd, J=7.33, 1.77 Hz, 1 H)
42%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; Inert atmosphere
Stage #2: at 20℃;
20.2) 3-Bromo-1-methyl-1 H-pyridin-2-one (intermediate 63): To a solution of 3-bromo-pyridin-2-ol (2.06g, 11.5 mmol.) in DMF (10 ml) was added NaH (60percent, 0.5Og, 12.64 mmol.) portionwise at O0C under argon. After 30 min methyl iodide (0.79 ml, 12.64 mmol.) was added dropwise and the reaction mixture was stirred <n="76"/>for 15 h at RT. The mixture was diluted with ethyl acetate (100 ml), washed with water (2x 200ml) and brine (100 ml), dried over Na2SO4 and evaporated under reduced pressure. The crude material was chromatographed on silica gel. Elution with ethyl acetate/cyclohexane from 0 to 50percent of ethyl acetate gave 0.92g of intermediate 63, yield = 42percent, yellow oil.
352 mg With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1 h; A mixture of iodomethane (1.22 g), 3-bromopyridin-2-ol (500 mg), potassium carbonate (1.19 g) and N,N-dimethylformamide (2 mL) was stirred at 80°C for 1 hr.
The reaction mixture was added to water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (352 mg).
MS (API+): [M+H]+ 187.9.
757 mg With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1 h; A mixture of 2-hydroxy-3-bromopyridine (Aldrich, 967 mg, 5.56 mmol), potassium carbonate(1536 mg, 11.12 mmol) and iodomethane (0.521 mL, 8.34 mmol) in DMF (10 mL) was stirred for1 h at rt, diluted in EtOAc/water, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (50percent EtOAc/hexane) to afford the title compound (757 mg) as a yellow oil. Rf= 0.11 (50percent EtOAc/hexane); Rt: 0.50 mm (LC-MS 1);MS mlz: 188.0 [M](LC-MS 1).

Reference: [1] Patent: US2010/184767, 2010, A1, . Location in patent: Page/Page column 24-25
[2] Patent: WO2014/122474, 2014, A1, . Location in patent: Page/Page column 48
[3] Patent: WO2009/103440, 2009, A1, . Location in patent: Page/Page column 73-74
[4] Patent: US2014/73651, 2014, A1, . Location in patent: Paragraph 0734; 0752; 0753
[5] Patent: EP2873669, 2015, A1, . Location in patent: Paragraph 0502; 0503
[6] Patent: WO2015/75665, 2015, A1, . Location in patent: Page/Page column 85.1
  • 11
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  • [ 77-78-1 ]
  • [ 81971-38-2 ]
Reference: [1] Journal of the American Chemical Society, 1982, vol. 104, # 15, p. 4142 - 4146
  • 12
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  • [ 74-88-4 ]
  • [ 13472-59-8 ]
Reference: [1] Heterocycles, 1990, vol. 31, # 5, p. 819 - 824
  • 13
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  • [ 74-88-4 ]
  • [ 13472-59-8 ]
Reference: [1] Patent: US6110914, 2000, A,
  • 14
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  • [ 98-80-6 ]
  • [ 24228-13-5 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 23, p. 6002 - 6005
  • 15
  • [ 13466-43-8 ]
  • [ 637348-81-3 ]
YieldReaction ConditionsOperation in experiment
96% With N-iodo-succinimide In acetonitrile; trifluoroacetic acid at 20℃; for 15 h; Example 142a
3-Bromo-5-iodopyridin-2-ol 142a
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with acetonitrile (50 mL), TFA (10 mL), 3-bromopyridin-2-ol (4.0 g, 11.56 mmol), N-iodosuccinimide (5.2 g, 11.56 mmol).
The mixture was stirred at room temperature for 15 h.
The mixture was diluted with water (100 mL) and resulting white solid was collected by filtration to afford 142a (6.6 g, 96percent) as a white solid. MS-ESI: [M+H]+ 300
96% With N-iodo-succinimide; trifluoroacetic acid In acetonitrile at 20℃; for 15 h; Example 214a
3-Bromo-5-iodopyridin-2-ol 214a
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with acetonitrile (50 mL), trifluoroacetic acid (10 mL), 3-bromopyridin-2-ol (4.0 g, 11.56 mmol) and N-iodosuccinimide (5.2 g, 11.56 mmol).
The mixture was stirred at room temperature for 15 h.
The mixture was diluted with water (100 mL) and resulting white solid was collected by filtration to afford 214a (6.6 g, 96percent) as a white solid. MS-ESI: [M+H]+ 300
85% With N-iodo-succinimide In acetonitrile for 1 h; Heating / reflux Following a previously reported method (Meana A, et al, Synlett 2003,1678-1682) compound 18 was prepared from N-iodosuccinimide (2.48 g, 11.0 mmol) and 3-bromo-2-hydroxypyridine 17 (1.74 g, 10.0 mmol) as a pale <n="48"/>brown solid ( 2.55 g, 85percent). 1H NMR (DMSO-(I6) δ 12.21 (br s, IH), 8.08 (d, IH, J= 2.3 Hz), 7.71 (d, IH, J= 2.3 Hz).
Reference: [1] Patent: US2013/116246, 2013, A1, . Location in patent: Paragraph 0467
[2] Patent: EP2773638, 2015, B1, . Location in patent: Paragraph 0844; 0845
[3] Synlett, 2003, # 11, p. 1678 - 1682
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 9, p. 2157 - 2165
[5] Patent: WO2007/126733, 2007, A2, . Location in patent: Page/Page column 33; 46-47
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