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Chemical Structure| 100-48-1
Chemical Structure| 100-48-1
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Product Details of [ 100-48-1 ]

CAS No. :100-48-1 MDL No. :MFCD00006417
Formula : C6H4N2 Boiling Point : -
Linear Structure Formula :- InChI Key :GPHQHTOMRSGBNZ-UHFFFAOYSA-N
M.W : 104.11 Pubchem ID :7506
Synonyms :
Chemical Name :4-Cyanopyridine

Calculated chemistry of [ 100-48-1 ]      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 : 0.0
Molar Refractivity : 28.95
TPSA : 36.68 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) : -6.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.14
Log Po/w (XLOGP3) : 0.46
Log Po/w (WLOGP) : 0.95
Log Po/w (MLOGP) : -0.23
Log Po/w (SILICOS-IT) : 1.37
Consensus Log Po/w : 0.74

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.33
Solubility : 4.87 mg/ml ; 0.0467 mol/l
Class : Very soluble
Log S (Ali) : -0.8
Solubility : 16.5 mg/ml ; 0.159 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.04
Solubility : 0.954 mg/ml ; 0.00916 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.25

Safety of [ 100-48-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312+P330-P302+P352+P312-P304+P340+P312-P362+P364-P501 UN#:N/A
Hazard Statements:H302-H312-H332 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 100-48-1 ]

* 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 [ 100-48-1 ]
  • Downstream synthetic route of [ 100-48-1 ]

[ 100-48-1 ] Synthesis Path-Upstream   1~31

  • 1
  • [ 100-48-1 ]
  • [ 64-17-5 ]
  • [ 41050-96-8 ]
Reference: [1] Bulletin de la Societe de Pharmacie de Lille, 1956, p. 39,42
[2] Polish Journal of Chemistry, 2001, vol. 75, # 9, p. 1237 - 1245
[3] Patent: WO2008/71404, 2008, A1, . Location in patent: Page/Page column 36
  • 2
  • [ 100-48-1 ]
  • [ 584-08-7 ]
  • [ 41050-96-8 ]
Reference: [1] Patent: US4406897, 1983, A,
  • 3
  • [ 100-48-1 ]
  • [ 802294-64-0 ]
  • [ 1531-18-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
  • 4
  • [ 100-48-1 ]
  • [ 64-17-5 ]
  • [ 1531-18-6 ]
Reference: [1] Chemistry Letters, 1984, p. 769 - 772
[2] Chemistry Letters, 1984, p. 769 - 772
[3] Chemistry Letters, 1984, p. 769 - 772
  • 5
  • [ 100-48-1 ]
  • [ 67-56-1 ]
  • [ 2459-09-8 ]
  • [ 1453-82-3 ]
  • [ 35451-46-8 ]
Reference: [1] ACS Catalysis, 2015, vol. 5, # 6, p. 3470 - 3477
  • 6
  • [ 100-48-1 ]
  • [ 67-56-1 ]
  • [ 2459-09-8 ]
Reference: [1] Synthetic Communications, 2003, vol. 33, # 19, p. 3461 - 3466
[2] Synthetic Communications, 2006, vol. 36, # 19, p. 2883 - 2886
  • 7
  • [ 100-48-1 ]
  • [ 7677-24-9 ]
  • [ 29181-50-8 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14733 - 14737
  • 8
  • [ 100-48-1 ]
  • [ 536-33-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
  • 9
  • [ 100-48-1 ]
  • [ 14222-60-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
  • 10
  • [ 100-48-1 ]
  • [ 54-85-3 ]
  • [ 1453-82-3 ]
Reference: [1] Molecules, 2000, vol. 5, # 2, p. 118 - 126
  • 11
  • [ 100-48-1 ]
  • [ 54-85-3 ]
Reference: [1] Patent: US2830994, 1956, ,
  • 12
  • [ 110-89-4 ]
  • [ 100-48-1 ]
  • [ 2767-90-0 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 12, p. 2667 - 2669
  • 13
  • [ 100-48-1 ]
  • [ 98-80-6 ]
  • [ 3034-31-9 ]
YieldReaction ConditionsOperation in experiment
73% With potassium <i>tert</i>-butylate; copper(ll) bromide In <i>tert</i>-butyl alcohol at 20℃; for 37 h; General procedure: A 10 mL round-bottomed flask was charged with the appropriate nitrile 2 (0.50 mmol), arylboronic acid 1(0.60 mmol), CuBr2 (6 mg, 5molpercent), t-BuOK (168 mg, 1.50 mmol), and t-BuOH (3.0 mL), and the mixture was stirred at r.t. until the reaction was complete (TLC). H2O (4.0 mL) was added, and the mixture was extracted with EtOAc (3 ×10 mL). The combined organic layers were washed twice with H2O,dried (Na2SO4), and concentrated to give a residue that was purified by column chromatography (silica gel, PE–EtOAc).
Reference: [1] Synthesis (Germany), 2017, vol. 49, # 8, p. 1834 - 1838
  • 14
  • [ 100-48-1 ]
  • [ 94805-51-3 ]
Reference: [1] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 10-11
[2] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 11
[3] Patent: EP1801102, 2007, A1, . Location in patent: Page/Page column 11
  • 15
  • [ 100-48-1 ]
  • [ 541-50-4 ]
  • [ 37398-49-5 ]
YieldReaction ConditionsOperation in experiment
71.9% With ammonium peroxydisulfate; sulfuric acid; silver nitrate In dichloromethane; waterReflux Step 1 : 2-Acetylisonicotinonitrile To a solution of isonicotinonitrile (52 g, 0.5 mol) in dichloromethane (1300 mL) and water (1 100 mL) were added ammonium persulfate ((NH4)2S208) (170 g, 0.75 mol), silver nitrate (6.8 g, 0.04 mol) and aqueous sulfuric acid (40 mL, 98percent sulfuric acid in 400 mL). A solution of 3-oxo-butyric acid (1 10 g, 1.25 mol) in dichloromethane (100 mL) was added dropwise while keeping the mixture refluxing. The reaction mixture was refluxed for 2 h. The resulting mixture was basified to pH -8-9 using sodium carbonate powder. The mixture was filtered and the filtrate was extracted with dichloromethane (500 mL x 3). The combined organics were dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to afford 2-acetylisonicotinonitrile (52.0 g, 71.9percent).
Reference: [1] Patent: WO2013/150416, 2013, A1, . Location in patent: Page/Page column 117
  • 16
  • [ 100-48-1 ]
  • [ 127-17-3 ]
  • [ 37398-49-5 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 8, p. 2866 - 2869
  • 17
  • [ 100-48-1 ]
  • [ 56-41-7 ]
  • [ 37398-49-5 ]
Reference: [1] Organic Letters, 2016, vol. 18, # 15, p. 3738 - 3741
  • 18
  • [ 100-48-1 ]
  • [ 72-19-5 ]
  • [ 37398-49-5 ]
Reference: [1] Organic Letters, 2016, vol. 18, # 15, p. 3738 - 3741
  • 19
  • [ 100-48-1 ]
  • [ 431-03-8 ]
  • [ 37398-49-5 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1982, # 10, p. 2801 - 2815
[2] Journal of Chemical Research, Miniprint, 1982, # 10, p. 2801 - 2815
  • 20
  • [ 617-35-6 ]
  • [ 100-48-1 ]
  • [ 97316-50-2 ]
  • [ 97316-54-6 ]
  • [ 97316-52-4 ]
  • [ 97316-53-5 ]
Reference: [1] Angewandte Chemie, 1985, vol. 97, # 8, p. 694 - 695
[2] Heterocycles, 1987, vol. 26, # 3, p. 731 - 744
[3] Angewandte Chemie, 1985, vol. 97, # 8, p. 694 - 695
[4] Angewandte Chemie, 1985, vol. 97, # 8, p. 694 - 695
[5] Heterocycles, 1987, vol. 26, # 3, p. 731 - 744
[6] Heterocycles, 1987, vol. 26, # 3, p. 731 - 744
[7] Heterocycles, 1987, vol. 26, # 3, p. 731 - 744
  • 21
  • [ 100-54-9 ]
  • [ 100-48-1 ]
  • [ 79-06-1 ]
  • [ 57963-11-8 ]
Reference: [1] Patent: US4672121, 1987, A,
  • 22
  • [ 100-48-1 ]
  • [ 67-56-1 ]
  • [ 51454-63-8 ]
YieldReaction ConditionsOperation in experiment
39%
Stage #1: for 0.5 h; Heating / reflux
Stage #2: With ammonium peroxydisulfate In water for 1.5 h; Heating / reflux
Stage #3: With potassium carbonate In water
Sulfuric acid (1.5 ml) was added to the solution of 4-cyanopyridine (15.7 g, 151 mmol) in methanol (225 ml) at room temperature and refluxed for 30 minutes. A solution of ammonium peroxodisulfate (54.9 g, 241 mmol) in H2O (100 ml) was slowly added over 30 minutes under reflux and the mixture was refluxed with stirring for 1 hour. After cooling, precipitated materials were filtered off and methanol was removed from the filtrate under reduced pressure. The residue was neutralized (pH = 9) by adding saturated aqueous K2CO3 solution and precipitated materials were filtered off again. The filtrate was extracted with chloroform (100 ml x 4), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica (chloroform/methanol) to give 2- (hydroxymethyl)isonicotinonitrile (7.95 g, 39 percent, off-white solid).
28%
Stage #1: With ammonium persulfate; sulfuric acid In water for 24 h; Heating / reflux
Stage #2: at 0℃;
Add ammonium persulfate (70.1 g, 307 mmol) to a solution of isonicotinonitrile (16.00 g, 154 mmol) in methanol: water: sulfuric acid (275 mL:135 mL:l 1 mL). Heat solution to reflux. After 24 hours, pour reaction onto ice and neutralize with ammonium hydroxide (70 ml). Extract solution with chloroform (3x600 ml). Combine the organic layers, dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with acetone :dichloromethane (1:6) to yield the title compound as a white solid (5.86 g, 28percent): 1H NMR (CDCl3) δ 3.17 (t, IH), 4.84 (d, IH), 7.45 (m, IH), 7.58 (s, IH), 8.74 (d, IH)
5.08 g With sulfuric acid; ammonium peroxodisulfate In water for 14 h; Reflux A)
2-(hydroxymethyl)isonicotinonitrile
To a solution of 4-cyanopyridine (10.4 g) in methanol (180 mL), a solution of conc. sulfuric acid (6.98 mL) in water (90 mL) and ammonium peroxodisulfate (45.6 g) were successively added at room temperature, and the mixture was heated under reflux for 14 hr.
The solvent was evaporated under reduced pressure, and 28percent aqueous ammonia (40 mL) was added.
The reaction mixture was extracted with a mixed solvent of ethyl acetate and THF, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.08 g) as a pale-yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 4. 62 (2H, d, J = 5.8 Hz), 5.63 (1H, t, J = 5.8 Hz), 7.73 (1H, d, J = 4.9 Hz), 7.80 (1H, s), 8.75 (1H, d, J = 5.0 Hz).
Reference: [1] European Journal of Organic Chemistry, 2017, vol. 2017, # 41, p. 6239 - 6245
[2] Patent: WO2008/8398, 2008, A2, . Location in patent: Page/Page column 356
[3] Patent: WO2006/57860, 2006, A1, . Location in patent: Page/Page column 136
[4] Tetrahedron, 1985, vol. 41, # 3, p. 617 - 620
[5] Patent: EP2816023, 2014, A1, . Location in patent: Paragraph 0406
  • 23
  • [ 100-48-1 ]
  • [ 7285-11-2 ]
  • [ 7664-93-9 ]
  • [ 51454-63-8 ]
Reference: [1] Patent: US4385058, 1983, A,
  • 24
  • [ 100-48-1 ]
  • [ 7664-93-9 ]
  • [ 51454-63-8 ]
Reference: [1] Patent: US6043248, 2000, A,
  • 25
  • [ 100-48-1 ]
  • [ 68325-15-5 ]
YieldReaction ConditionsOperation in experiment
53%
Stage #1: With 2,2,6,6-tetramethyl-piperidine In tetrahydrofuran at -78 - 25℃; for 0.5 h;
Stage #2: With hexachloroethane In tetrahydrofuran at -78℃; for 0.5 h;
To a stirred solution of 2,2,6,6-tetramethyl piperidine (17.16 mL, 100.854 mmol) in THF (100 mL) was added n-BuLi (2.17 M, 44.26 mL, 96.052 mmol) at -30°C. After stirring the mixture for 15 mm at 25°C, it was cooled to -78°C and 4-cyanopyridine (5 g, 48.026 mmol) in THF (40 mL) was added dropwise. After stirring the reaction mixture for 30 mm at -78°C, hexachioroethane (23.87 g, 100.854 mmol) in THF (50 mL) was added at -78°C. The resulting mixture was stirred for 30 mm at -78°C and was quenched with saturated NH4C1 solution. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (4 x 300 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude material which was purified by column chromatography using silica (100-200 mesh) and 5percent EtOAc-hexane as eluent to afford 3-chloropyridine-4-carbonitrile (3.5 g, 25.26 1 mmol, 53percent) as pale white solid. GCMS: 138 (mlz).
Reference: [1] Tetrahedron, 2006, vol. 62, # 25, p. 5862 - 5867
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10118 - 10129
[3] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 182; 183
[4] Tetrahedron Letters, 2005, vol. 46, # 1, p. 135 - 137
[5] Journal of the American Chemical Society, 2013, vol. 135, # 24, p. 9213 - 9219
  • 26
  • [ 100-48-1 ]
  • [ 13958-98-0 ]
Reference: [1] Tetrahedron, 2009, vol. 65, # 4, p. 748 - 751
[2] Organic Letters, 2011, vol. 13, # 9, p. 2306 - 2309
[3] Tetrahedron Letters, 2005, vol. 46, # 1, p. 135 - 137
  • 27
  • [ 123-75-1 ]
  • [ 100-48-1 ]
  • [ 2456-81-7 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 12, p. 2667 - 2669
  • 28
  • [ 100-48-1 ]
  • [ 111042-91-2 ]
Reference: [1] Patent: WO2014/186035, 2014, A1,
  • 29
  • [ 100-48-1 ]
  • [ 135048-32-7 ]
  • [ 577778-58-6 ]
YieldReaction ConditionsOperation in experiment
87.1%
Stage #1: at 25℃; for 1 h;
Stage #2: for 0.166667 h;
Stage #3: at 80℃; for 7 h; Reflux
100 ml of anhydrous ethanol was put into a 500 ml reaction flask, and sliced sodium was added.Stir the reaction to prepare sodium ethoxide. After the reaction is complete, continue stirring for 1 hour. Add 10.8 g of 4-cyanopyridine, control the temperature at 25°C and stir for 1 hour. Add acetic acid to adjust the pH to 5.0.Stir for 10 minutes,Added 14 g of the intermediate 2-cyanoisonicotinic acid hydrazide prepared in Example 1,Start oil bath heating and circulation, reflux temperature 80 °C, reflux 7h, HPLC monitoring,When the raw material 2-cyanoisonicotinic acid hydrazide obtained by the peak area normalization method is ≤ 0.5percent,Stop the heating and circulation, release the heat transfer oil in the jacket, wait until the temperature drops below 30°C, feed and centrifuge, and filter cake is rinsed twice with 50 ml of ethanol. The filter cake was transferred to an enamel baking dish and dried under reduced pressure (80°C/<-0.9 MPa/8h) to obtain 18 g of solid with a yield of 87.1percent.
85.6% With sodium methylate In methanol for 8 h; Reflux The 4-cyano pyridine 11.5g (110mmol) dissolved in 500 ml methanol, then adding sodium methoxide 3.5g, stir to dissolve. Then add 2-cyano [...] 16.2g (100mmol), heating reflux for 8 hours. After the reaction, the separated solid filter, vacuum drying after washing with methanol, to obtain he holds a department 21.4g, yield 85.6percent, purity 99.5percent (HPLC).
78% With sodium methylate In methanol for 10 h; Reflux A solution of 1.04 g (10 mmol) of the compound of the formula (2) in 50 ml of methanol was added with sodium methoxide 50mg, stirring to dissolve. Then, 1.62 g (10 mmol) of the compound of the formula (3) 2-cyanoisoniazide was added and the mixture was refluxed for 10 hours Time. After the completion of the reaction, the precipitated solid was filtered off, washed with methanol and dried with vacuum chestnut to give a yellow powdery product Pisitatum (1.93 g, yield 78percent, HPLC purity (normalized method): 98.5percent.
Reference: [1] Patent: CN107573330, 2018, A, . Location in patent: Paragraph 0039; 0040-0042; 0065; 0067; 0069; 0071; 0073-0076
[2] Patent: CN105566301, 2016, A, . Location in patent: Paragraph 0064; 0065
[3] Patent: CN104151297, 2016, B, . Location in patent: Paragraph 0049; 0050
  • 30
  • [ 100-48-1 ]
  • [ 577778-58-6 ]
Reference: [1] Patent: WO2016/134854, 2016, A1,
[2] Patent: WO2016/134854, 2016, A1,
[3] Patent: WO2016/134854, 2016, A1,
[4] Patent: CN108101840, 2018, A,
  • 31
  • [ 100-48-1 ]
  • [ 654663-32-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10118 - 10129
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