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Product Details of [ 13466-38-1 ]

CAS No. :13466-38-1 MDL No. :MFCD00234042
Formula : C5H4BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :NDMZZQRNZFWMEZ-UHFFFAOYSA-N
M.W : 174.00 Pubchem ID :599528
Synonyms :

Calculated chemistry of [ 13466-38-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 33.96
TPSA : 33.12 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) : -6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.62
Log Po/w (XLOGP3) : 1.52
Log Po/w (WLOGP) : 1.55
Log Po/w (MLOGP) : 0.99
Log Po/w (SILICOS-IT) : 1.64
Consensus Log Po/w : 1.46

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.43
Solubility : 0.644 mg/ml ; 0.0037 mol/l
Class : Soluble
Log S (Ali) : -1.82
Solubility : 2.61 mg/ml ; 0.015 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.3
Solubility : 0.876 mg/ml ; 0.00504 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.45

Safety of [ 13466-38-1 ]

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

Application In Synthesis of [ 13466-38-1 ]

* 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 [ 13466-38-1 ]
  • Downstream synthetic route of [ 13466-38-1 ]

[ 13466-38-1 ] Synthesis Path-Upstream   1~49

  • 1
  • [ 1072-97-5 ]
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Reference: [1] Heterocycles, 2002, vol. 57, # 1, p. 55 - 71
[2] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 489[3] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
[4] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 2, p. 353 - 357[5] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 2, p. 413 - 417
[6] Patent: WO2016/65582, 2016, A1, . Location in patent: Page/Page column 56
  • 2
  • [ 142-08-5 ]
  • [ 13466-38-1 ]
Reference: [1] Patent: US5939439, 1999, A,
[2] Patent: WO2018/193387, 2018, A1, . Location in patent: Page/Page column 107
  • 3
  • [ 39856-50-3 ]
  • [ 13466-38-1 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 4, p. 577 - 579
  • 4
  • [ 142-08-5 ]
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  • [ 13466-43-8 ]
Reference: [1] Synthesis, 2001, # 14, p. 2175 - 2179
  • 5
  • [ 13472-85-0 ]
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Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
  • 6
  • [ 51933-78-9 ]
  • [ 13466-38-1 ]
  • [ 85330-62-7 ]
  • [ 98627-15-7 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
  • 7
  • [ 624-28-2 ]
  • [ 13466-38-1 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
[2] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 70,73
  • 8
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  • [ 13466-38-1 ]
Reference: [1] Journal of the American Chemical Society, 1949, vol. 71, p. 70,73
  • 9
  • [ 856849-02-0 ]
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  • [ 874493-49-9 ]
Reference: [1] Journal of the American Chemical Society, 1949, vol. 71, p. 70,73
  • 10
  • [ 109-09-1 ]
  • [ 13466-38-1 ]
Reference: [1] Patent: WO2018/193387, 2018, A1,
  • 11
  • [ 1072-97-5 ]
  • [ 1493-13-6 ]
  • [ 13466-38-1 ]
  • [ 475106-12-8 ]
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 28, p. 3771 - 3773
[2] Tetrahedron Letters, 2014, vol. 55, # 28, p. 3771 - 3773
  • 12
  • [ 504-29-0 ]
  • [ 13466-38-1 ]
Reference: [1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 489[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
  • 13
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  • [ 56673-34-8 ]
YieldReaction ConditionsOperation in experiment
96% With Lawessons reagent In toluene for 1 h; Inert atmosphere; Reflux Lawesson's reagent (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 2.32 g, 5.74 mmol) was added in portions to a suspension of 5-bromo-2(1H)-pyridone (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 2 g, 11.5 mmol) in dry toluene (50 mL) under nitrogen. The reaction mixture was heated at reflux for 1 h and then cooled to room temperature. The product that precipitated on cooling was collected by filtration and dried under high vacuum to give 5-bromo-pyridine-2-thiol (2.1 g, 96percent), which was used directly in the next step without further purification.
Reference: [1] Patent: US2012/309796, 2012, A1, . Location in patent: Page/Page column 25
[2] Patent: WO2007/39580, 2007, A1, . Location in patent: Page/Page column 36
[3] Patent: WO2007/39578, 2007, A1, . Location in patent: Page/Page column 42
[4] Patent: WO2007/39581, 2007, A1, . Location in patent: Page/Page column 32
  • 14
  • [ 13466-38-1 ]
  • [ 56673-34-8 ]
Reference: [1] Chemical Communications, 2017, vol. 53, # 27, p. 3850 - 3853
[2] Chemical Communications, 2017, vol. 53, # 44, p. 5997 - 6000
  • 15
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Reference: [1] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
  • 16
  • [ 142-08-5 ]
  • [ 13466-38-1 ]
  • [ 13466-43-8 ]
Reference: [1] Synthesis, 2001, # 14, p. 2175 - 2179
  • 17
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YieldReaction ConditionsOperation in experiment
96.78%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h;
Stage #2: for 3 h;
To a suspension of NaH (4.8 g, 0.2 mol) in THF (10 mL) was added a solution of 5-bromopyridin-2(1H)-one (8.6 g, 0.05 mol) in THF (120 mL) at 0° C. The resulting mixture was stirred for 1 h and CH3I (35.5 g, 0.25 mol) was added. The mixture was stirred for 3 h. The reaction was quenched with aqueous NH4Cl solution. The organic phase was concentrated to give the crude product, which was purified by column chromatography to give 5-bromo-1-methylpyridin-2(1H)-one (8.9 g, 96.78percent). 1H NMR (CDCl3): δ=3.5 (S, 3H), 6.52 (m, 1H), 7.32 (m, 1H), 7.45 (m, 1H).
96.78% With sodium hydride In tetrahydrofuran at 0℃; for 4 h; To a suspension of NaH (4.8 g, 0.2 mol) in THF (10 mL) was added a solution of 5-bromopyridin-2(1H)-one (8.6 g, 0.05 mol) in THF (120 mL) at 0 C. The resulting mixture was stirredfor 1 h and CH3I (35.5 g, 0.25 mol) was added. The mixture was stirred for 3 h. The reaction wasquenched with aqueous NH4Cl solution. The organic phase was concentrated to give the crude product,which was purified by column chromatography to give 5-bromo-1-methylpyridin-2(1H)-one (8.9 g,96.78 percent). 1H NMR (CDCl3): δ= 3.5 (S, 3H), 6.52 (m, 1H), 7.32 (m, 1H),7.45(m, 1H).
93%
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).
21% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h; Step 3: 5-Brom -l-methylpyridin-2(lH)-one To a solution of 5-bromopyridin-2(lH)-one (0.18 g, 1.03 mmol) in DMF (5 niL) was added iodomethane (0.2 niL, 3.1 mmol) and potassium carbonate (0.8 g, 6.2 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, the residue dissolved in ethyl acetate (200 mL), washed with water (50 mL) and brine solution. The organic layers were combined and dried over sodium sulfate, filtered and concentrated under vacuum to afford 5-bromo-l-methylpyridin-2(lH)-one [Albrecht, US Patent Application Publication No. 2009/0318436] as yellow solid (40

Reference: [1] Patent: US2010/331320, 2010, A1, . Location in patent: Page/Page column 56
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3649 - 3657
[3] Synlett, 2015, vol. 26, # 11, p. 1557 - 1562
[4] Patent: WO2013/49559, 2013, A1, . Location in patent: Page/Page column 68
[5] Patent: WO2005/44195, 2005, A2, . Location in patent: Page/Page column 40
[6] Patent: WO2005/40151, 2005, A1, . Location in patent: Page/Page column 56-57
[7] Patent: WO2008/8539, 2008, A2, . Location in patent: Page/Page column 117
[8] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7076 - 7080
[9] Patent: WO2013/49565, 2013, A1, . Location in patent: Page/Page column 73
[10] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 2993 - 2997
[11] Patent: WO2005/44195, 2005, A2, . Location in patent: Page/Page column 40
  • 18
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YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In <i>N</i>-methyl-acetamide; water Reference Example 1
5-Bromo-1-methyl-2(1H)-pyridone
With cooling with ice, potassium carbonate (5.96 g, 43.1 mmol) and methyl iodide (1.29 mL, 20.7 mmol) were added to a dimethylformamide (50 mL) solution of 5-bromo-2-hydroxypyridine (3.0 g, 7.24 mmol), and stirred at that temperature for 16 hours.
Water was added to the reaction mixture, and extracted three times with ethyl acetate.
The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified through silica gel column chromatography (C-300, ethyl acetate/hexane = 1/1) to obtain the entitled compound (2.92 g, 90 percent) as a colorless oil.
Reference: [1] Patent: WO2006/59778, 2006, A1, . Location in patent: Page/Page column 57
[2] Patent: EP1820797, 2007, A1,
[3] Justus Liebigs Annalen der Chemie, 1931, vol. 486, p. 71,78
[4] Patent: WO2007/106349, 2007, A2, . Location in patent: Page/Page column 72-73
  • 19
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YieldReaction ConditionsOperation in experiment
12g With silver carbonate In benzene at 50℃; for 16 h; Silver carbonate (16.0 g, 57.8 mmol) and methyl iodide (6.5 mL, 103 mmol) were sequentially added to a solution of 5-bromopyridin-2(1H)-one (15.0 g, 86.2 mmol) in benzene (225 mL). The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was filtered through celite and concentrated. Purification by chromatography using 1-5percent ethyl acetate in pet ether provided 12 g of the desired compound: 1H NMR (300 MHz, CDCl3) 8.15-8.25 (narrow m, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 3.92 (s, 3H).
12 g With silver carbonate In benzene at 50℃; for 16 h; Silver carbonate (16.0 g, 57.8 mmol) and methyl iodide (6.5 mL, 103 mmol) were sequentially added to a solution of 5-bromopyridin-2(1H)-one (15.0 g, 86.2 mmol) in benzene (225 mL).
The mixture was stirred for 16 h at 50° C.
After cooling to room temperature, the mixture was filtered through celite and concentrated.
Purification by chromatography using 1-5percent ethyl acetate in pet ether provided 12 g of the desired compound: 1H NMR (300 MHz, CDCl3) 8.15-8.25 (narrow m, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 3.92 (s, 3H).
Reference: [1] Heterocycles, 1990, vol. 31, # 5, p. 819 - 824
[2] Patent: US2015/210671, 2015, A1, . Location in patent: Paragraph 0173; 0179; 0180
[3] Patent: US9145393, 2015, B2, . Location in patent: Page/Page column 29; 30; 37
  • 20
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  • [ 870521-31-6 ]
YieldReaction ConditionsOperation in experiment
76% With potassium carbonate In dimethyl sulfoxide at 20℃; for 4 h; Reference Example 17
Production of 5-bromo-2-isopropoxypyridine
5-Bromopyridin-2(1H)-one (5 g, 28.7 mmol) and potassium carbonate (9.93 g, 71.8 mmol) were mixed in dimethyl sulfoxide, and at room temperature, 2-iodoisopropyl (3.73 ml, 37.3 mmol) was added thereto, and stirred at room temperature for 4 hours.
The reaction solution was diluted with ethyl acetate, and washed with water and saturated saline in that order.
The organic layer was dried with sodium sulfate, and the solvent was evaporated off under reduced pressure.
The residue was purified through silica gel column chromatography (elude: ethyl acetate/hexane = 20/80 to 50/50) to obtain the entitled compound (4.72 g, 76 percent) as a colorless oily substance.
1H-NMR (400 MHz, CDCl3) δ:1.33 (6H, d, J=6.3 Hz), 5.18-5.28 (1H, m), 6.59 (1H, d, J=8.8 Hz), 7.61 (1H, dd, J=8.8, 2.9 Hz), 8.17 (1H, d, J=2.0 Hz)
52% With silver carbonate In toluene at 50℃; for 16 h; AgC03 (1.3 g, 5 mmol), toluene (15 mL) and 2-iodopropane (1.2 mL, 12 mmol) were added to 5-bromopyridin-2(lm-one (1.74 g, 10 mmol). The mixture was stirred at 50 °C for 16 h, after which it was allowed to cool, then diluted with EtOAc and filtered through Celite(at). The filter cake was washed with EtOAc and the combined filtrates concentrated and purified by distillation to yield the sub-title compound (1.12 g, 52percent).
Reference: [1] Patent: EP1892241, 2008, A1, . Location in patent: Page/Page column 124
[2] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 761 - 767
[3] Patent: WO2005/123675, 2005, A1, . Location in patent: Page/Page column 54
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YieldReaction ConditionsOperation in experiment
59% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24 h; Synthesis of S-Methoxy-pyrrolidine-S-carboxylic acid r3-(6-isopropoxy-pyridin-3- VlH H-indazol-5-yll-amide <n="220"/>Step 1 :5-bromo-1 H-pyridone 1 Bl (10Og, 0.58 mol), potassium carbonate (238g, 1.73mol) and 2-iodopropane (86ml, 0.86mol) were stirred in DMF (1 L) at r.t. for 1 day. The mixture were diluted with ethyl acetate and water, layers were separated. The separated organic layer was washed with water (X2), dried (Mg SO4) and filtered. Solvents were removed in vacuum and column purification [5percent ethyl acetate in hexanes] gave first the less polar 5-isopropoxypyridine 2BIa (73g, 59percent) as colourless liquid. Continuous elution with [50percent ethyl acetate in hexanes] gave the more polar 5- bromo-1 -isopropylpyridone 2BIb as white solid (22g, 18percent).
Reference: [1] Organic Letters, 2015, vol. 17, # 14, p. 3382 - 3385
[2] Patent: WO2009/105500, 2009, A1, . Location in patent: Page/Page column 218-219
[3] Patent: WO2016/100147, 2016, A1, . Location in patent: Page/Page column 5; 8
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Reference: [1] Patent: WO2016/161160, 2016, A1, . Location in patent: Paragraph 0159
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  • [ 67443-38-3 ]
Reference: [1] Patent: WO2007/102059, 2007, A1,
  • 24
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  • [ 100-39-0 ]
  • [ 83664-33-9 ]
YieldReaction ConditionsOperation in experiment
95% With silver carbonate In benzene at 50℃; for 24 h; To a solution of 5-bromopyridin-2 (1E-ONE (100 mmol, 17. 4 g, 1. 0 eq.) in benzene (170 mL) was added silver (I) carbonate (67. 0 mmol, 18. 5 g, 0. 67 eq.). The flask was wrapped with aluminum foil and then benzyl bromide (120 mmol, 20. 5 g, 1. 2 eq.) was added via syringe in a steady stream. The mixture was heated to 50 °C and stirred in the dark for approximately 24 hours. LC/MS of the reaction mixture indicates two peaks both with M+H = 265 corresponding to the desired molecular weight. On the basis of relative polarities, the more polar peak was thought to be the N-alkylated product and consisted of approximately 20 percent of the total. The reaction mixture was allowed to cool to room temperature and the silver salt was removed by filtration of the mixture through a pad of celite. The filter cake was washed with benzene and the organic layer was washed twice with 2percent sodium bicarbonate and twice with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified on a Biotage Sp4 65i over a gradient of 5-95percent hexanes in ethyl acetate to afford the title compound as a golden oil (25. 1 g, 95percent). LRMS : 265 (M+H) +. H NMR (DMSO-D6, 400 MHz) ; 8. 29 (1 H, s) 7. 72 (1 H, D, J=8. 5 Hz) 7. 31-7. 43 (5 H, m) 6. 54 (1 H, d, J=8. 5Hz) 5. 34 (2 H, s)
95% With silver carbonate In toluene at 100℃; To a solution of 5-bromopyridin-2(1 H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwiseand the reaction mixture was stirred at 100 °C over night. The reaction mixture was filteredthrough a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1 .8 g, 95percent).
95% With silver carbonate In toluene at 100℃; To a solution of 5-bromopyridin-2(1H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwise and the reaction mixture was stirred at 100° C. over night. The reaction mixture was filtered through a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1.8 g, 95percent).
85% With silver carbonate In tetrahydrofuranReflux; Darkness To a solution of 1 (1.4 g, 8 mmol) in dry THF (80 mL) was added benzyl bromide (1.14 mL, 9.6 mmol) and Ag2CO3 (1.32 g, 4.8 mmol) and subsequently refluxed in the dark overnight. The reaction mixture was filtered through celite and concentrated to provide brown solid which was flash chromatographed on silica gel eluting with 10percent EtOAc in hexanes to provide 1.8 g (85percent) of a white solid;1H NMR (CDCl3) δ (ppm) 5.34 (s, 2H), 6.71 (d, 1H, J = 8.7 Hz), 7.25-7.44 (m, 5H), 7.64 (dd, 1H, J = 8.8 Hz), 8.20 (d, 1H, J = 2.5 Hz); MS (ESI) m/z 289 (M+Na)+.

Reference: [1] Heterocycles, 1990, vol. 31, # 5, p. 819 - 824
[2] Patent: WO2004/92145, 2004, A1, . Location in patent: Page 148-149
[3] Patent: WO2014/13469, 2014, A1, . Location in patent: Page/Page column 37; 38
[4] Patent: US2014/163036, 2014, A1, . Location in patent: Paragraph 0204-0205
[5] Tetrahedron Letters, 2005, vol. 46, # 27, p. 4621 - 4625
[6] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 20, p. 5924 - 5934
  • 25
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YieldReaction ConditionsOperation in experiment
99%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 0.0833333 h; Inert atmosphere; Cooling with ice
Stage #2: at 20℃; for 1 h;
Example 117; Preparation of 5-(2-(benzyloxy)pyridin-5-yl)-3-(3-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)benzyl)-5-methylimidazolidine-2,4-dione; 117-a) Preparation of 5-(2-(benzyloxy)pyridin-5-yl)-5-methylimidazolidine-2,4-dione; 117-a-1) Preparation of 5-bromo-2-(benzyloxy)pyridine; 2-Hydroxy-5-bromopyridine (1.00 g, 5.75 mmol) was dissolved in N,N'-dimethylformamide (23 mL), and the resultant mixture was added with sodium hydride (purity 50percent) (253 mg, 6.32 mmol) under an argon atmosphere under ice-cold conditions. Five minutes later, the resultant mixture was added with benzyl bromide (6.82 mL, 6.90 mmol) at the same temperature, and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=1/1). 5-Bromo-2-(benzyloxy)pyridine (1.51 g, yield 99percent) was obtained as a pale yellow solid.1H-NMR (CDCl3) δ: 5.10 (2H, s), 6.54 (1H, d, J=9.5 Hz), 7.28-7.39 (7H, m).
Reference: [1] Patent: US2010/48610, 2010, A1, . Location in patent: Page/Page column 66
[2] European Journal of Organic Chemistry, 2007, # 24, p. 4038 - 4049
[3] Patent: WO2009/70869, 2009, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2007/84560, 2007, A2, . Location in patent: Page/Page column 158
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YieldReaction ConditionsOperation in experiment
92% With N-ethyl-N,N-diisopropylamine; zinc(II) oxide; zinc(II) chloride In 1,4-dioxane at 110℃; Inert atmosphere General procedure: To a solution of substituted 2-oxo-1,2-dihydropyridines (3.36 mmol), zinc oxide (0.30 g, 3.70 mmol),zinc chloride (0.50 g, 3.70 mmol), N,N-diisopropylethylamine (0.48 g, 3.70 mmol), 1,4-dioxane (15 mL)was added benzyl chloride (0.58 g, 4.04 mmol) under argon atmosphere. The mixture was heated in 110 °C oil bath with rapid stirring for the indicated time. The reactor was cooled to room temperature,and the insoluble residue was filtered off through celite, and the cake was wash with ethyl acetate(30 mL). The filtrate was washed with water (10 mL 2), once with brine (10 mL), dried overmagnesium sulfate, filtered, and concentrated in vacuo to afford crude product. The product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:20) to yield thecorresponding compounds.
Reference: [1] Molecules, 2018, vol. 23, # 7,
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Reference: [1] Organic Letters, 2015, vol. 17, # 14, p. 3382 - 3385
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Reference: [1] Organic Letters, 2015, vol. 17, # 14, p. 3382 - 3385
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  • [ 83664-33-9 ]
Reference: [1] Patent: US2005/187266, 2005, A1,
  • 30
  • [ 13466-38-1 ]
  • [ 15862-34-7 ]
Reference: [1] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 117
  • 31
  • [ 13466-38-1 ]
  • [ 13472-60-1 ]
Reference: [1] Patent: US2015/210671, 2015, A1,
[2] Patent: US9145393, 2015, B2,
  • 32
  • [ 13466-38-1 ]
  • [ 75-03-6 ]
  • [ 63785-87-5 ]
YieldReaction ConditionsOperation in experiment
44%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5 h;
Stage #2: at 20℃;
A solution of 5-bromo-1,2-dihydropyridin-2-one (1.04 g, 6 mmol) in DMF (12 mL) was treated with sodium hydride (60percent dispersion in mineral oil, 960 mg, 24 mmol) at room temperature and then stirred 30 minutes.
Iodoethane (0.58 mL, 7.2 mmol) was added to the mixture and the reaction was stirred overnight at room temperature.
This operation was repeated twice, until the reaction was completed.
The middle was diluted with water and DCM.
The organic layer was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (DCM/MeOH 98/2) to give compound (145a) (532 mg, 2.63 mmol, 44percent).
Reference: [1] Patent: EP2913330, 2015, A1, . Location in patent: Paragraph 0526
[2] Patent: WO2011/154677, 2011, A1, . Location in patent: Page/Page column 111-112
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 2993 - 2997
  • 33
  • [ 74-96-4 ]
  • [ 13466-38-1 ]
  • [ 63785-87-5 ]
YieldReaction ConditionsOperation in experiment
74% With potassium carbonate In N,N-dimethyl-formamide at 18 - 25℃; To a solution of 5-bromopyridin-2(1H)-one (1.0 g, 6.0 mmol) and K2C03 (2.0 g, 15 mmol) in DMF (10 mL) was added ethyl bromide (0.7 g, 7.5 mmol). The resulting mixture wasstirred overnight at room temperature. Afterward, the mixture was diluted with ethyl acetate (50 mL), washed with H20 (50 mL) and brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether /ethyl acetate (20/1) to afford 0.9 g (74percent) of the title product as a brown oil. LC/MS: mlz 202 [M+H]
Reference: [1] Patent: WO2016/46260, 2016, A1, . Location in patent: Paragraph 257
  • 34
  • [ 13466-38-1 ]
  • [ 75-03-6 ]
  • [ 63785-87-5 ]
YieldReaction ConditionsOperation in experiment
3.5 g
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.666667 h;
Stage #2: at 20℃; for 15 h;
To a solution of 5-bromo-2(7H)-pyridone (5.97 g, 34.3 mmol, Sigma- Aldrich, St. Louis, MO) in DMF (40 mL) at 0 °C was added sodium hydride (60percent dispersion in mineral oil (1.65 g, 41.2 mmol, Sigma-Aldrich, St. Louis, MO) in one portion. The resulting mixture was stirred at 0 °C for 40 min and was treated with iodoethane (3.32 mL, 41.2 mmol, Sigma-Aldrich, St. Louis, MO). The reaction mixture was stirred at room temperature for 15 h, and was quenched with saturated NaHC03 solution. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, concentrated and purified by flash chromatography (80 g RediSep® Rf column, gradient elution from hexanes to 60percent EtOAc/hexanes) to provide the desired product that was contaminated with some residual DMF. The mixture was dried under high vacuum at 75 °C for 12 h to provide 5-bromo-l-ethylpyridin-2(7H)- one (3.5 g) as a pale yellow oil.
1.8 g With potassium carbonate In acetonitrile at 20℃; Inert atmosphere [00315] A round bottom flask was charged with 2-Hydroxy-5-bromopyridine (3.00 g, 17.2 mmol), iodoethane (6.93 mL, 86.2 mmol), potassium carbonate (11.92 g, 86.2 mmol) in acetonitrile (30 mL) under argon. The reaction mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was taken in water and extracted with ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate. The solvents were removed and the residue was purified by flash chromatography (40g silica, 0-100percent ethyl acetate in hexanes) to give a beige solid (1.8 g). LC/MS: [M+] and [M+2] 202.2, 204.1; 1H NMR (300 MHz, CDC13): δ 7.40 (d, J=2.4 Hz, 1H), 7.35-7.31 (m, 1H), 6.48 (d, J=9.9 Hz, 1H), 3.99-3.91 (m, 2 H), 1.35 (t, J=7.4 Hz, 3H).
Reference: [1] Patent: WO2010/19899, 2010, A1, . Location in patent: Page/Page column 214
[2] Patent: US2013/53362, 2013, A1, . Location in patent: Paragraph 0997; 0998
[3] Patent: WO2013/173382, 2013, A1, . Location in patent: Page/Page column 227
[4] Patent: WO2017/190086, 2017, A1, . Location in patent: Paragraph 00315
  • 35
  • [ 13466-38-1 ]
  • [ 74-96-4 ]
  • [ 63785-87-5 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 2, p. 353 - 357[2] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 2, p. 413 - 417
  • 36
  • [ 13466-38-1 ]
  • [ 98-80-6 ]
  • [ 76053-45-7 ]
YieldReaction ConditionsOperation in experiment
100 mg With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In toluene at 100℃; for 1 h; Microwave irradiation A)
5-phenylpyridin-2(1H)-one
A mixture of 5-bromopyridin-2(1H)-one (500 mg), phenylboronic acid (385 mg), tetrakis(triphenylphosphine)palladium(0) (498 mg), 2M aqueous sodium carbonate solution (2.87 mL) and toluene (7.0 mL) was stirred at 100° C. for 1 hr under microwave irradiation.
The reaction mixture was cooled to room temperature, and filtered through celite.
To the filtrate was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.
The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg).
1H NMR (400 MHz, CDCl3) δ 6.71 (1H, d, J=9.2 Hz), 7.31-7.36 (1H, m), 7.42-7.43 (4H, m), 7.65 (1H, d, J=2.4 Hz), 7.80 (1H, dd, J=9.4, 2.6 Hz), 13.62 (1H, brs).
Reference: [1] Patent: US2013/137675, 2013, A1, . Location in patent: Paragraph 0697; 0698
  • 37
  • [ 13466-38-1 ]
  • [ 381233-75-6 ]
YieldReaction ConditionsOperation in experiment
92.6% With N-iodo-succinimide In acetonitrile at 82℃; for 0.333333 h; Will contain 5-bromo-2-hydroxypyridine (2.5 g, 14.4 mmol), A mixture of iodosuccinimide (4.7 g, 20.9 mmol) and acetonitrile (40 mL) was stirred at 82 ° C for 20 min. After cooling to room temperature, filtration, the cake was recrystallized from ethyl acetate to give 5-bromo-2-hydroxy-3-iodopyridine (65) (4.0 g). The yield was 92.6percent.
83% With N-iodo-succinimide In acetonitrile for 4 h; Reflux To 5-bromo-2-hydroxypyridine I (5g, 29mmol) was added solid N Jodosuccinimide (7.lg, 32mmol) in acetonitrile (l2OmL). The solution was stirred at reflux for 4 hours and followed by TLC. The solution was cooled to room temperature, filteredand washed with methanol. 5-bromo-2-hydroxy-3-.iodopyridine 2 was obtained as a pink solid (yield: 83percent).
33% With N-iodo-succinimide In N,N-dimethyl-formamide at 50℃; for 6 h; Synthesis of 5-bromo-3-iodopyridin-2-ol (218): 5-Bromopyridin-2-ol (1.74 g, 10 mmol) was dissolved in DMF (40 mL) and NIS (2.7 g, 12 mmol) was added at room temperature. The reaction mixture was heated at 50 °C for 6 h. The reaction mixture was cooled down to room temperature, poured into 50 mL of water, extracted with EtOAc (60 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give 5-bromo-3-iodopyridin-2-ol (218) as yellow solid (1.0 g, 33percent yield). LCMS: m/z 301.9 [M+H]+; tR = 1.34 min.
Reference: [1] Patent: CN108084186, 2018, A, . Location in patent: Paragraph 0187-0188
[2] Synlett, 2003, # 11, p. 1678 - 1682
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 4, p. 1644 - 1668
[4] Patent: WO2015/132727, 2015, A1, . Location in patent: Page/Page column 22; 28
[5] Heterocycles, 2002, vol. 57, # 1, p. 55 - 71
[6] Patent: WO2015/3166, 2015, A1, . Location in patent: Paragraph 00691
  • 38
  • [ 13466-38-1 ]
  • [ 381233-75-6 ]
YieldReaction ConditionsOperation in experiment
86% With N-iodo-succinimide In toluene at 90℃; for 0.333333 h; Inert atmosphere To a solution of 5-bromo-2-(1H)-pyridone (18.8 gf 10.8 mmol) in dry toluene {400 ml_) was added N-iodosuccinimide (24.3 g, 10.8 mmol) under nitrogen. The reaction mixture was stirred at 90 °C for 20 minutes then cooled to 25 °C. The precipitate was filtered off and washed with methanol, dried under vacuum to give the pink-orange color solid 28.0 g (86percent). 1H NMR (300 MHz, CDCi3 ) δ 8.1 (s, 1 H), 7.6 (s, 1 H). Mass caicuiated for formula C5H3BrINO 298.84, observe MS ES+: 300.0/302.0.
Reference: [1] Patent: WO2010/118207, 2010, A1, . Location in patent: Page/Page column 282-283
  • 39
  • [ 13466-38-1 ]
  • [ 874959-68-9 ]
Reference: [1] Patent: US2012/309796, 2012, A1,
  • 40
  • [ 13466-38-1 ]
  • [ 871839-91-7 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 761 - 767
[2] Patent: WO2005/123675, 2005, A1,
[3] Patent: WO2009/105500, 2009, A1,
  • 41
  • [ 13466-38-1 ]
  • [ 871839-91-7 ]
Reference: [1] Patent: WO2016/161160, 2016, A1,
  • 42
  • [ 13466-38-1 ]
  • [ 1002309-52-5 ]
Reference: [1] Patent: WO2014/210255, 2014, A1,
  • 43
  • [ 13466-38-1 ]
  • [ 1002309-52-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 2993 - 2997
  • 44
  • [ 13466-38-1 ]
  • [ 73183-34-3 ]
  • [ 1054483-78-1 ]
YieldReaction ConditionsOperation in experiment
64% With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine In 1,4-dioxane at 110℃; Sealed tube A solution of 5-bromopyridin-2-ol SM1 (0.1 g, 0.57 mmol), 4,4,4,4,5,5,5,5-octamethyl- 2,2-bi(1,3,2-dioxaborolane) SM2 (0.88 g, 3.45 mmol), Tricyclohexyl phosphine (0.032 g, 0.114mmol), Pd2(dba)3 (0.052 g, 0.057 mmol) and KOAc (0.17 g, 1.71 mmol) dissolved with dioxane (10 mL) in sealed tube was stirred at 110 °C overnight. After consumption of the starting material (by LC-MS), the solvent from reaction mixture was removed under reduced pressure, the residue was diluted with brine and extracted with EtOAc. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain cmde product, which waspurified by silica gel column chromatography to afford compound 3 (0.08 g, 64percent) as a black liquid.TLC: 50percent EA/PE.
Reference: [1] Patent: WO2016/44770, 2016, A1, . Location in patent: Page/Page column 644
  • 45
  • [ 13466-38-1 ]
  • [ 2926-30-9 ]
  • [ 76041-79-7 ]
YieldReaction ConditionsOperation in experiment
60% With H2O8S2*2H3N; C42H34F10IrN4(1+)*F6P(1-) In dimethyl sulfoxide at 40℃; for 0.5 h; Flow reactor; UV-irradiation General procedure: In an oven-dried vial equipped with a magnetic stirrer and a PTFE septum, [Ir{dF(CF3)ppy}2](dtbpy)]PF6 (5.6 mg, 1 molpercent) was added to a mixture of the substrate (0.5 mmol, 1 equiv), CF3SO2Na (1.5 mmol, 3 equiv), and (NH4)2S2O8 (0.5 mmol, 1 equiv) in DMSO (5 mL). The solution was pumped into the Vapourtec photoreactor (fluoropolymer tube, 1.3 mm i.d., 10 mL) and the liquid flowrate was set at 0.33 mL/min (30 min residence time). The reactor was irradiated with 54 blue LEDs (450 nm, total power 24 W). The reaction mixture collected from the outlet was diluted with H2O and extracted with Et2O (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude was then pre-adsorbed onto silica, dried in vacuo, and purified by flash chromatography to yield the trifluoromethylated product.
Reference: [1] Synthesis (Germany), 2017, vol. 49, # 22, p. 4978 - 4985
  • 46
  • [ 13466-38-1 ]
  • [ 1349151-98-9 ]
Reference: [1] Patent: WO2011/143426, 2011, A1,
  • 47
  • [ 13466-38-1 ]
  • [ 1349151-98-9 ]
Reference: [1] Patent: WO2011/143399, 2011, A1,
  • 48
  • [ 13466-38-1 ]
  • [ 928653-73-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 4, p. 1644 - 1668
[2] Patent: WO2015/132727, 2015, A1,
  • 49
  • [ 13466-38-1 ]
  • [ 1333222-12-0 ]
Reference: [1] Patent: US2014/274703, 2014, A1,
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