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[ CAS No. 614-96-0 ] {[proInfo.proName]}

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Chemical Structure| 614-96-0
Chemical Structure| 614-96-0
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Product Details of [ 614-96-0 ]

CAS No. :614-96-0 MDL No. :MFCD00005680
Formula : C9H9N Boiling Point : -
Linear Structure Formula :- InChI Key :YPKBCLZFIYBSHK-UHFFFAOYSA-N
M.W : 131.17 Pubchem ID :11978
Synonyms :

Calculated chemistry of [ 614-96-0 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.11
Num. rotatable bonds : 0
Num. H-bond acceptors : 0.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.26
TPSA : 15.79 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) : -5.39 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.7
Log Po/w (XLOGP3) : 2.41
Log Po/w (WLOGP) : 2.48
Log Po/w (MLOGP) : 1.89
Log Po/w (SILICOS-IT) : 3.06
Consensus Log Po/w : 2.31

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.84
Solubility : 0.191 mg/ml ; 0.00145 mol/l
Class : Soluble
Log S (Ali) : -2.38
Solubility : 0.542 mg/ml ; 0.00413 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.63
Solubility : 0.0305 mg/ml ; 0.000232 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 614-96-0 ]

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 [ 614-96-0 ]

* 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 [ 614-96-0 ]
  • Downstream synthetic route of [ 614-96-0 ]

[ 614-96-0 ] Synthesis Path-Upstream   1~17

  • 1
  • [ 614-96-0 ]
  • [ 1196-79-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 24, p. 9480 - 9497
  • 2
  • [ 614-96-0 ]
  • [ 68-12-2 ]
  • [ 52562-50-2 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: at 0℃; for 1 h;
Stage #2: at 20℃; for 5 h;
Stage #3: With sodium hydroxide In N,N-dimethyl-formamide at 100℃; for 0.166667 h;
General procedure: Oxalyl chloride (0.3 mL) was added in a drop-wise manner to cooled (ice-bath) DMF (3 mL) under stirring. The mixture was then stirred at 0 °C for 1 h. A solution of the substituted indole (4 mmol) in DMF (1.5 mL) was then added to the reaction mixture in a dropwise manner. The resulting mixture was stirred at room temperature for 5 h. A 2 N solution of sodium hydroxide (2 mL) was then added, and the mixture was heated at 100 °C for 10 min. The mixture was then cooled and extracted with ethyl acetate (3 X 50 mL). The organic layers were combined and washed with sequentially water and brine. The organics were dried (Na2SO4) and distilled to dryness to give the crude residue, which was purified by flash column chromatography using ethyl acetate/petroleum ether (3:1, v/v) as the eluent to give pure indole-3-carbaldehyde (4a-k).
90%
Stage #1: at 0 - 20℃; for 1.5 h;
Stage #2: at 0℃; for 1 h; Heating / reflux
Example 3; 1. Synthesis of 3-cyanoindole derivatives with a terminal carboxylic acid; A basic synthetic method of a derivative with a terminal carboxylic acid is shown in the following scheme. [Show Image] An objective compound was prepared by (1) formylation of 3-position of the corresponding indole using phosphorus oxychloride in the presence of dimethylformamide (Vilsmeier method), (2) cyanation by dehydrating reaction with hydroxylamine in sodium formate and formic acid, (3) coupling with ethyl 4-fluorobenzoate in the presence of potassium fluoride on almina and 18-crown-5-ether in dimethylsulfoxide and then, (4) hydrolysis with lithium hydroxide in total 4 steps in that order. The results are shown in the following Table 1. In addition, XO-CH146 (R=H) was prepared from the third step using 3-cyanoindole purchased.; 1. Synthesis of XO-CH164 XO-CH155; Under an argon atmosphere, 5-methyl indole (1.04 g, 7.93 mmol) was dissolved in dimethylformamide (10 mL), and to the solution was added dropwise phosphorus oxychloride (2mL) under ice-cooling, and the resulting mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added dropwise an aqueous sodium hydroxide solution (5 g/15 mL) under ice-cooling, and the mixture was heated for reflux for an hour. The reaction mixture was adjusted to pH2 to 3 with concentrated hydrochloric acid under ice-cooling, and then, the solid was collected by filtration and dried at 60°C under reduced pressure to give XO-CH155 as a pale pink solid (1.13 g, 90percent yield).
74% at 0 - 40℃; for 1.5 h; General procedure: Phosphorus oxychloride (0.42 g, 2.74 mmol) was added dropwise to a solution of the indole 5b, 5e–5g (0.30 g, 2.29 mmol) in DMF (0.84 g, 11.4 mmol) at 0 °C for 30 min. The solution was then heated at 40 °C for 1 h. Ice was added to the reaction vessel, followed by a solution of sodium hydroxide (2 M). The solution was refluxed for 40 min. The mixture was cooled and extracted using ethyl acetate, and the organic phase was washed with brine. The organic extracts were combined, dried over Na2SO4, and concentrated. The crude residue was purified by chromatography on a silica gel column using hexane-ethyl acetate as an eluent to obtain the desired product [19].
71.5%
Stage #1: at 0℃; for 0.666667 h; Inert atmosphere
Stage #2: at 0 - 35℃; for 1.33333 h;
Stage #3: With sodium hydroxide In water; N,N-dimethyl-formamide at 100℃; for 0.5 h; Cooling with ice
General procedure: To a 100 mL three-necked round flask was introduced anhydrous N,N-dimethylformamide (4.2 mL, 34.35 mmol) at 0 °C under argon followed by slow addition of phosphorus oxychloride (1.3 mL, 13.62 mmol). Solution was mixed at 0 °C for 40 min. A solution of 5-methyl-1H-indole (1.627 g, 12.41 mmol) in 2.5 mL of DMF was slowly added maintaining the temperature below 10 °C. The solution was stirred for 40 min at 0 °C and then 35 °C for additional 40 min. Then ice was added to the flask and a solution of sodium hydroxide (5.5 g, 137.25 mmol dissolved in 14.6 mL of water) was introduced using a dropping funnel. Solution was vigorously stirred during the addition, then heated to 100 °C for 30 min and left to reach room temperature. The brown precipitate was filtered off and washed with large volumes of water. The powder was dried in vacuum. Yield 71.5percent. 1H NMR (DMSO-d6, 400 MHz): δ 2.41 (s, 3H), 7.07 (d, 1H, J = 8.4 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.90 (s, 1H), 8.32 (s, 1H), 9.89 (s, 1H), 12.01 (s, 1H); MS (ESI), m/z: 158.10 [M - H]-.

Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 158 - 167
[2] Patent: EP1932833, 2008, A1, . Location in patent: Page/Page column 11; 12
[3] Chemistry - A European Journal, 2016, vol. 22, # 2, p. 716 - 723
[4] Marine Drugs, 2014, vol. 12, # 4, p. 1757 - 1772
[5] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 70 - 81
[6] Organic and Biomolecular Chemistry, 2014, vol. 12, # 48, p. 9764 - 9768
[7] Journal of the Chemical Society, 1958, p. 3493,3494
[8] Farmaco, 1994, vol. 49, # 6, p. 443 - 448
[9] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 7, p. 1301 - 1305
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 6, p. 1793 - 1798
[11] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 8, p. 2342 - 2346
[12] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 3780 - 3790
[13] Tetrahedron Letters, 2012, vol. 53, # 17, p. 2222 - 2225
[14] Angewandte Chemie - International Edition, 2013, vol. 52, # 11, p. 3250 - 3254[15] Angew. Chem., 2013, vol. 125, # 11, p. 3332 - 3336,5
[16] Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11881 - 11885[17] Angew. Chem., 2014, vol. 126, # 44, p. 12075 - 12079,5
[18] Organic Letters, 2015, vol. 17, # 12, p. 3186 - 3189
[19] Chemistry - A European Journal, 2015, vol. 21, # 43, p. 15104 - 15107
[20] Organic and Biomolecular Chemistry, 2018, vol. 16, # 36, p. 6647 - 6651
[21] European Journal of Medicinal Chemistry, 2016, vol. 112, p. 289 - 297
  • 3
  • [ 110-18-9 ]
  • [ 614-96-0 ]
  • [ 52562-50-2 ]
YieldReaction ConditionsOperation in experiment
70% With water; iodine; oxygen; sodium carbonate In 1,4-dioxane at 100℃; for 36 h; Schlenk technique; Sealed tube General procedure: Under air, a 20 mL of Schlenk tube equipped with a stir bar was charged with indole 1 (0.2 mmol, 1 equiv),TMEDA (75 µL, 0.5 mmol, 2.5 equiv), Na2CO3 (42.4 mg, 0.4mmol, 2.0 equiv), 1,4-dioxane (0.5 mL) and H2O (100 µL). Then I2 (101.5 mg, 0.4 mmol, 2.0 equiv) was added and the tube was sealed with a rubber plug and charged with O2. The reaction mixture was stirred at 100 °C for 36 h in oil bath. After cooling to room temperature, the resultant mixture was evaporated with EtOAc (20 mL) under reduced pressure and the residue was purified by flash column chromatography on a silica gel to give the products.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 41, p. 5618 - 5621
  • 4
  • [ 100-97-0 ]
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  • [ 52562-50-2 ]
YieldReaction ConditionsOperation in experiment
92% With iodine; oxygen; pyrographite In N,N-dimethyl-formamide at 120℃; for 0.8 h; General procedure: A 50 mL round bottom flask equipped with a magnetic stirring bar was charged with substituted indole 1 (1.0 mmol, 1.0 equiv), HMTA (2.0 mmol, 0.2803 g, 2.0 equiv), activated carbon (0.1 g) and DMF (2 mL). Then I2 (0.2 mmol, 0.0507g, 20 molpercent) was added and the flask was equipped with a reflux condenser. The reaction mixture was stirred at 120 oC under open air and monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature. The resultant mixture was filtered through a pad of celite and the filter cake was washed thoroughly with EtOAc (4 × 6 mL). The filtrate was washed with 0.5 M aqueous HCl (10 mL), saturated NaHCO3 solution (10 mL) and saturated NaCl solution ( 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with hexane and ethyl acetate to give the product.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 30, p. 2877 - 2880
  • 5
  • [ 50-00-0 ]
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  • [ 52562-50-2 ]
YieldReaction ConditionsOperation in experiment
90% With iron(III) chloride; ammonia In water; N,N-dimethyl-formamide at 130℃; for 1 h; General procedure: A 50 mL round-bottomed flask equipped with a magnetic stirringbar was charged with the appropriate indole 1 (0.5 mmol,1.0 equiv), 37percent aq HCHO (0.5 mmol, 0.0406 g, 1.0 equiv), 25percent aqNH3 (1.0 mmol, 0.0681 g, 2.0 equiv), FeCl3 (0.01 mmol, 0.0016 g,2 molpercent), and DMF (2 mL). The flask was fitted with a reflux condenser,and the mixture was stirred at 130 °C under open air.When the reaction was complete (TLC), the mixture was cooledto r.t., diluted with sat. aq NaCl (10 mL) and 0.5 M aq HCl (2 mL),and extracted with EtOAc (3 x 7 mL). The organic layers werecombined, washed with sat. aq NaHCO3 (10 mL) and sat. aq NaCl(10 mL), dried (Na2SO4), and concentrated under reduced pressure.The residue was purified by flash column chromatography(silica gel, hexane–EtOAc).
Reference: [1] Synlett, 2017, vol. 28, # 19, p. 2670 - 2674
  • 6
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  • [ 298-12-4 ]
  • [ 52562-50-2 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 20, p. 3707 - 3710
  • 7
  • [ 614-96-0 ]
  • [ 100-61-8 ]
  • [ 52562-50-2 ]
Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 31, p. 11924 - 11927
  • 8
  • [ 614-96-0 ]
  • [ 52562-50-2 ]
Reference: [1] Patent: US6433175, 2002, B1,
  • 9
  • [ 67-66-3 ]
  • [ 614-96-0 ]
  • [ 52562-50-2 ]
Reference: [1] Journal of Biological Chemistry, 1925, vol. 62, p. 507
[2] Biochemical Journal, 1935, vol. 29, p. 546,549
  • 10
  • [ 124-38-9 ]
  • [ 614-96-0 ]
  • [ 10242-02-1 ]
YieldReaction ConditionsOperation in experiment
97 %Spectr. With lithium tert-butoxide In N,N-dimethyl-formamide at 100℃; for 24 h; General procedure: In a dried two-necked test tube was charged with LiOtBu (160 mg, 2.00 mmol) and indole 1a (23.4 mg, 0.4 mmol). The reaction vessel was evacuated under high vacuum and the atmosphere was replace with a balloon of CO2. Then DMF (2 mL) was added and the mixture was stirred for 24 h at 100°C. Then the result mixture was cooled and carefully quenched with a solution of HCl (2 N) and extracted with EtOAc (5x). The combined organic layers were washed with water (2x), brine (1x) and dry over MgSO4. The dried organics were concentrated under reduce pressure and the residue was purified by preparative TLC (hexane:acetone = 1:1) to afford the desired product 2a (153.0 mg, 95percent) as a white solid.
Reference: [1] Organic Letters, 2012, vol. 14, # 20, p. 5326 - 5329,4
[2] Heterocycles, 2015, vol. 90, # 2, p. 1196 - 1204
  • 11
  • [ 614-96-0 ]
  • [ 10242-02-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 11, p. 2734 - 2737
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 17, p. 7293 - 7316
  • 12
  • [ 614-96-0 ]
  • [ 15719-64-9 ]
  • [ 10242-02-1 ]
Reference: [1] Chemische Berichte, 1926, vol. 59, p. 2755
  • 13
  • [ 50-00-0 ]
  • [ 614-96-0 ]
  • [ 124-40-3 ]
  • [ 30218-58-7 ]
Reference: [1] Angewandte Chemie - International Edition, 2009, vol. 48, # 50, p. 9533 - 9537
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1954, vol. 297, p. 229,233
[3] Journal of the Chemical Society, 1948, p. 705,708
  • 14
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  • [ 1912-47-6 ]
Reference: [1] Tetrahedron Letters, 1994, vol. 35, # 19, p. 3013 - 3016
[2] Journal of the American Chemical Society, 2012, vol. 134, # 26, p. 10815 - 10818
  • 15
  • [ 614-96-0 ]
  • [ 2941-78-8 ]
Reference: [1] Synthetic Communications, 2010, vol. 40, # 23, p. 3480 - 3487
[2] Applied Organometallic Chemistry, 2011, vol. 25, # 1, p. 34 - 46
  • 16
  • [ 614-96-0 ]
  • [ 227960-12-5 ]
Reference: [1] Patent: US6492406, 2002, B1,
[2] Organic Letters, 2012, vol. 14, # 20, p. 5326 - 5329,4
[3] Organic Letters, 2016, vol. 18, # 15, p. 3918 - 3921
  • 17
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  • [ 914348-94-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2016, vol. 112, p. 289 - 297
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