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[ CAS No. 18677-48-0 ] {[proInfo.proName]}

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Chemical Structure| 18677-48-0
Chemical Structure| 18677-48-0
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Product Details of [ 18677-48-0 ]

CAS No. :18677-48-0 MDL No. :MFCD01646188
Formula : C7H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :LPFKVVZTNDJALE-UHFFFAOYSA-N
M.W : 139.15 Pubchem ID :817733
Synonyms :

Calculated chemistry of [ 18677-48-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.29
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 37.22
TPSA : 31.35 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) : -6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.94
Log Po/w (XLOGP3) : 0.79
Log Po/w (WLOGP) : 1.1
Log Po/w (MLOGP) : -0.13
Log Po/w (SILICOS-IT) : 1.32
Consensus Log Po/w : 1.0

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.51
Solubility : 4.28 mg/ml ; 0.0307 mol/l
Class : Very soluble
Log S (Ali) : -1.03
Solubility : 13.0 mg/ml ; 0.0935 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.25
Solubility : 0.779 mg/ml ; 0.0056 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.74

Safety of [ 18677-48-0 ]

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 [ 18677-48-0 ]

* 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 [ 18677-48-0 ]
  • Downstream synthetic route of [ 18677-48-0 ]

[ 18677-48-0 ] Synthesis Path-Upstream   1~9

  • 1
  • [ 124-41-4 ]
  • [ 84476-99-3 ]
  • [ 18677-48-0 ]
YieldReaction ConditionsOperation in experiment
91% at 135℃; for 0.25 h; microwave To a vial charged with 2,5-difluoropyridine (127 mg, 1.1 mmol) was added a 25percent solution of sodium methoxide in methanol (2 mL). Upon completion of addition, the reaction mixture was heated at 135 0C under microwave conditions for 15 min. At the conclusion of this period, the reaction mixture was diluted with brine (5 mL) and extracted with EtOAc (3 x 5 mL). The combined extracts were dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 60percent EtOAc/hexanes to provide Intermediate 23 as a yellow oil (139 mg, 91percent). 1H NMR (400 MHz, CDCl3) δ ppm 3.80 (s, 6 H), 6.87 (t, J-2.20 Hz, 1 H), 7.78 (d, J=2.20 Hz, 2 H).
Reference: [1] Patent: WO2007/30582, 2007, A2, . Location in patent: Page/Page column 88
  • 2
  • [ 124-41-4 ]
  • [ 71902-33-5 ]
  • [ 18677-48-0 ]
YieldReaction ConditionsOperation in experiment
57% at 135℃; for 2 h; Microwave irradiation [0315] To a solution of 3,5-difluoropyridine (5.4 g, 46.8 mmol, 1 eq.) in MeOH (45 mL) was added NaOMe (7.5 g, 140.4 mmol). The mixture was divided into three microwave tubes and individually heated at 135 °C for 1 h in a microwave reactor. The three tubes were combined, concentrated, and diluted with a mixture EtOAc (100 mL) and brine (30 mL). The organic layerwas dried over Na2504 and concentrated. The crude was re-dissolved in MeOH (45 mL) and added NaOMe (7.5 g, 140.4 mmol). The mixture was again divided into three microwave tubes and individually heated at 135 °C for 1 h in a microwave reactor. The three tubes were combined and concentrated. The crude was dissolved in a mixture of EtOAc (200 mL) and brine (30 mL). The organic layer was dried over Na2SO4, concentrated, and purified on silica gelusing a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxypyridine (3.73 g, 57percent) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J— 2.4 Hz, 2H), 6.76 (t, J 2.4 Hz, 1H), 3.88 (s, 6H). LRMS (M+H+) m/z 140.1.
Reference: [1] Patent: WO2013/102145, 2013, A1, . Location in patent: Paragraph 0315
[2] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 321 - 326
  • 3
  • [ 2457-47-8 ]
  • [ 18677-48-0 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
[2] Patent: US4713080, 1987, A,
  • 4
  • [ 2457-47-8 ]
  • [ 865-33-8 ]
  • [ 18677-48-0 ]
Reference: [1] Journal of the American Chemical Society, 2002, vol. 124, # 1, p. 58 - 66
  • 5
  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 71902-33-5 ]
  • [ 18677-48-0 ]
YieldReaction ConditionsOperation in experiment
57% at 135℃; for 1 h; Microwave irradiation Step 1;To a solution of 3,5-difluoropyridine (5.4 g, 46.8 mmol, 1 eq.) in MeOH (45 mL) was added NaOMe (7.5 g, 140.4 mmol). The mixture was divided into three microwave tubes and individually heated at 135° C. for 1 h in a microwave reactor. The three tubes were combined, concentrated, and diluted with a mixture EtOAc (100 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated. The crude was re-dissolved in MeOH (45 mL) and added NaOMe (7.5 g, 140.4 mmol). The mixture was again divided into three microwave tubes and individually heated at 135° C. for 1 h in a microwave reactor. The three tubes were combined and concentrated. The crude was dissolved in a mixture of EtOAc (200 mL) and brine (30 mL). The organic layer was dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxypyridine (3.73 g, 57percent) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=2.4 Hz, 2H), 6.76 (t, J=2.4 Hz, 1H), 3.88 (s, 6H). LRMS (M+H+) m/z 140.1.
Reference: [1] Patent: US2015/344483, 2015, A1, . Location in patent: Paragraph 0582; 0583
  • 6
  • [ 2457-47-8 ]
  • [ 124-41-4 ]
  • [ 18677-48-0 ]
Reference: [1] Synthesis, 2005, # 15, p. 2590 - 2596
[2] Bulletin des Societes Chimiques Belges, 1986, vol. 95, # 11, p. 1009 - 1020
[3] Patent: US2006/156481, 2006, A1, . Location in patent: Page/Page column 9-10
  • 7
  • [ 625-92-3 ]
  • [ 124-41-4 ]
  • [ 18677-48-0 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1171,1174
  • 8
  • [ 18677-48-0 ]
  • [ 68-12-2 ]
  • [ 204862-70-4 ]
YieldReaction ConditionsOperation in experiment
62% With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 0.5 h; [0316] To a solution of 3,5-dimethoxypyridine (3.6 g, 25.90 mmol, 1 eq.) in THF (80 mL) was added BuLi (3Mhexanes, 13.0 mL, 38.85 mmol, 1.5 eq.) at-20 °C. The mixture was warmed to 0 °C, stirred at 0 °C for 30 mm, cooled back down to -78 °C, and added DMF (3.8 g, 51.8 mmol,2 eq.). The mixture was gradually warmed to 0 °C, quenched with NH4C1(saL) solution, and diluted with EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3 ,5-dimethoxyisonicotinaldehyde (2.7 g, 62percent) as a yellow solid. LRMS (M+H+) mz 168.1.
62%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -20 - 0℃; for 0.5 h;
Stage #2: at 0℃;
Step 2
To a solution of 3,5-dimethoxypyridine (3.6 g, 25.90 mmol, 1 eq.) in THF (80 mL) was added BuLi (3M/hexanes, 13.0 mL, 38.85 mmol, 1.5 eq.) at -20° C.
The mixture was warmed to 0° C., stirred at 0° C. for 30 min, cooled back down to -78° C., and added DMF (3.8 g, 51.8 mmol, 2 eq.).
The mixture was gradually warmed to 0° C., quenched with NH4Cl(sat.) solution, and diluted with EtOAc.
The aqueous layer was extracted with EtOAc twice.
The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxyisonicotinaldehyde (2.7 g, 62percent) as a yellow solid. LRMS (M+H+) m/z 168.1.
45%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78 - -70℃; for 0.5 h;
Stage #2: for 1 h;
To a stirred solution of lithium diisopropylamide ("LDA", 1.2 mmol) in THF (4 mL) at -78 0C was added a solution of Intermediate 23 (139 mg, 1.0 mmol) at a rate which kept the temperature below -70 0C. The reaction mixture was stirred for 30 minutes and then DMF (0.12 mL, 1.5 mmol) was added drop wise. Upon completion of addition, the reaction mixture was stirred for Ih and then diluted with EtOAc (10 mL). The resulting mixture was washed with satd NaHCO3 (5 mL), brine (5 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 70percent EtOAc/hexanes to provide Intermediate 24 as a pale yellow solid (75 mg, 45percent). 1H NMR (400 MHz, CDCl3) δ ppm 3.95 (s, 6 H), 8.11 (s, 2 H), 10.44 (s, 1 H).
Reference: [1] Patent: WO2013/102145, 2013, A1, . Location in patent: Paragraph 0316
[2] Patent: US2015/344483, 2015, A1, . Location in patent: Paragraph 0584; 0585
[3] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 321 - 326
[4] Patent: WO2007/30582, 2007, A2, . Location in patent: Page/Page column 89
  • 9
  • [ 18677-48-0 ]
  • [ 1033610-45-5 ]
YieldReaction ConditionsOperation in experiment
57%
Stage #1: With n-butyllithium In tetrahydrofuran; cyclohexane at -78 - 20℃; for 0.0833333 h;
Stage #2: With bromine In tetrahydrofuran; cyclohexane at -78 - 20℃; for 0.166667 h;
Stage #3: With water; sodium thiosulfate In tetrahydrofuran; cyclohexane
To a stirred solution of 3,5-dimethoxypyridine (2.7 g, 19.4 mmol) in dry THF at -780C was added ra-butyllithium (23.3 mmol, 2 M solution in cyclohexanes). During this addition a precipitate formed and the reaction was allowed to warm to room temperature for 5 minutes. The precipitate separated into an oily phase and the reaction was re-cooled and treated with bromine (1.5 ml, 29.1 mmol) and again allowed to warm to room temperature. After stirring for 10 minutes the solution became homogeneous and was quenched with 10percent Na2S2O3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated onto silica- gel under reduced pressure. The solid residue was purified by flash chromatography <n="87"/>(silica-gel, eluted sequentially with hexanes : EtOAc, 2:1, 1:1, 1:2) to give the product as a white solid (2.4 g, 57percent). 1H-NMR (300 MHz, CDCl3) δ 7.95 (s, 2H), 3.99 (s, 6H).
Reference: [1] Patent: WO2008/70908, 2008, A1, . Location in patent: Page/Page column 85-86
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