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Product Details of [ 15861-24-2 ]

CAS No. :15861-24-2 MDL No. :MFCD00005669
Formula : C9H6N2 Boiling Point : -
Linear Structure Formula :- InChI Key :YHYLDEVWYOFIJK-UHFFFAOYSA-N
M.W : 142.16 Pubchem ID :27513
Synonyms :

Calculated chemistry of [ 15861-24-2 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.01
TPSA : 39.58 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) : -6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.45
Log Po/w (XLOGP3) : 1.1
Log Po/w (WLOGP) : 2.04
Log Po/w (MLOGP) : 0.88
Log Po/w (SILICOS-IT) : 2.51
Consensus Log Po/w : 1.6

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.02
Solubility : 1.36 mg/ml ; 0.00955 mol/l
Class : Soluble
Log S (Ali) : -1.52
Solubility : 4.26 mg/ml ; 0.0299 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.34
Solubility : 0.0644 mg/ml ; 0.000453 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.36

Safety of [ 15861-24-2 ]

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 [ 15861-24-2 ]

* 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 [ 15861-24-2 ]
  • Downstream synthetic route of [ 15861-24-2 ]

[ 15861-24-2 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 1259448-44-6 ]
  • [ 15861-36-6 ]
  • [ 15861-24-2 ]
Reference: [1] Journal of the American Chemical Society, 2010, vol. 132, # 50, p. 17933 - 17944
  • 2
  • [ 15861-24-2 ]
  • [ 1670-81-1 ]
Reference: [1] Journal of Organic Chemistry, 1955, vol. 20, p. 1458
[2] Chinese Chemical Letters, 2010, vol. 21, # 12, p. 1407 - 1410
  • 3
  • [ 15861-24-2 ]
  • [ 15861-23-1 ]
YieldReaction ConditionsOperation in experiment
77% With triethylsilane In trifluoroacetic acid at 0℃; for 4 h; A solution of 5-cyanoindole (1 g, 7 mmol) in 10 mL TFA was cooled to 0° C. and then triethylsilane (1.6 g, 2 eq.) was added. The reaction mixture was stirred at 0° C. for 4 h then diluted with EtOAc and washed with 1M HCl solution. The aqueous layers were combined and neutralized with 50percent NaOH to pH10 then extracted 3.x. with EtOAc. These latter extracts were combined, washed with brine, dried and evaporated to yield the indoline (77percent).
67% With boron trifluoride diethyl etherate; sodium cyanoborohydride In methanol at 25℃; Dissolve 5-cyanoindole (142 mg, 1 mmol) and sodium cyanoborohydride (63 mg, 1 mmol) in methanol (2 ml). Boron trifluoride etherate (152 drops, 1.2 mmol) was added dropwise and allowed to react at room temperature for 2-3 hours. After quenching, add 25percent ammonia to quench. The reaction was followed by extraction with ethyl acetate (10 mL x 3 times). The organic layers were combined, dried over anhydrous magnesium sulfate, concentrated and subjected to column chromatography (oilEther: ethyl acetate = 10:1) was isolated to give 97 mg of the desired product in 67percent yield.
56% at 0 - 20℃; for 2 h; Triethylsilane (2.0 eq.) was slowly added to a solution of indole (1 .0 eq.) in trifluoroacetic acid (1 .4 M), cooled to 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then at r.t. for 1 h. Upon completion (monitored by TLC), the reaction was basified to pH 1 1 with NaOH (5.0 M) and extracted with EtOAc (x3). The organic layers were combined, washed with brine, dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired indoline. Following general procedure M, 5-cyanoindole (600.0 mg, 4.22 mmol) afforded indoline-5-carbonitrile (340.0 mg, 2.36 mmol, 56percent yield) as a light yellow solid. UPLC-MS (ES+, Short acidic): 1 .30 min, m/z 289.0 [2M+H]+.
40% With sodium cyanoborohydride In acetic acid at 20℃; A solution of 5-cyanoindole (3 g, 0.021 mol) in glacial acetic acid (25 mL) was treated portionwise with sodium cyanoborohydride (4 g, 0.063 mol) over 20-30 min then the solution was stirred overnight at rt under N2. The reaction was quenched by addition of water, and most of acetic acid was removed in vacuo. The residue was diluted with water and adjusted to pH>8 with 1M NaOH then extracted 3.x. with ethyl acetate. Extracts were combined and back extracted 2.x. with 1M HCl then set aside. (Starting indole can be recovered from these initial EtOAc extracts if desired.) Aqueous acid extracts were combined and rebasified with 5N NaOH, and then re-extracted with EtOAc. The latter extracts were combined, washed with brine, dried over anh. Na2SO4, filtered and evaporated to provide the indoline product (1.22 g, 40percent) as an off-white crystalline solid. 1H NMR (CDCl3, 300 MHz) δ 7.29-7.31 (m, 2H), 6.54 (d, 1H, J=8.4 Hz), 4.20 (bs, 1H), 3.67 (t, 2H, J=8.6 Hz), 3.06 (t, 2H, J=8.6 Hz)
33%
Stage #1: at 0 - 20℃; for 5 h;
Stage #2: With sodium hydroxide In water
Reference Example 7 2,3-dihydro-1H-indole-5-carbonitrile; To a solution (5 mL) cooled to 0°C in an ice bath of 1H-indole-5-carbonitrile (640 mg, 4.50 mmol) in acetic acid was added sodium cyanotrihydroborate (848 mg, 13.5 mmol). The reaction mixture was stirred at room temperature for 5 hr and diluted with water. The mixture was basified with 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was extracted with 1N hydrochloric acid and the aqueous layer was again basified with 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated. The residue was crystallization from ethyl acetate to give the title compound as pale-yellow crystals (213 mg, yield 33percent). 1H-NMR (300 MHz, CDCl3)δ:3.06 (t, J = 8.5 Hz, 2 H), 3.67 (t, J = 8.7 Hz, 2 H), 3.83 (br s, 1 H), 6.45 - 6.59 (m, 1 H), 7.24 - 7.33 (m, 2 H).

Reference: [1] Patent: US2004/220206, 2004, A1, . Location in patent: Page 25-26
[2] Journal of Materials Chemistry A, 2015, vol. 3, # 34, p. 17704 - 17712
[3] Patent: CN105085504, 2018, B, . Location in patent: Paragraph 0139; 0147-0150
[4] Patent: WO2014/188173, 2014, A1, . Location in patent: Paragraph 00239; 00521
[5] Patent: US2004/220206, 2004, A1, . Location in patent: Page 25
[6] Patent: EP2399914, 2011, A1, . Location in patent: Page/Page column 92
[7] Patent: US2012/252853, 2012, A1, . Location in patent: Page/Page column 22
  • 4
  • [ 15861-24-2 ]
  • [ 17380-18-6 ]
YieldReaction ConditionsOperation in experiment
84% With trichlorophosphate In <i>N</i>-methyl-acetamide; water Preparation 35
3-Formyl-1 H -indole-5-carbonitrile
Phosphoryl chloride (4.24ml, 45.48mmol) was added dropwise to dimethylformamide (3.52ml, 45.48mmol) and stirred for 30mins at room temperature.
A solution of 1H-indole-5-carbonitrile (5.39g, 37.9mmol) in dimethylformamide (10ml) was added dropwise.
A solid precipitated, further dimethylformamide (10ml) was added to aid stirring and the reaction mixture was then stirred at room temperature for 3hr.
Water was added to quench the reaction mixture which was then stirred for 18hr.
The stirring was stopped and the reaction mixture was left to stand, after 24hr a pink solid had precipitated in the organic layer.
The layers were separated and organic layer filtered, washed with water and dried to give the desired product (5.44g, 84percent).
1H NMR (DMSO)δ 7.60-7.80 (m, 2H), 8.20-8.30 (m, 2H), 10.00 (s, 1H), 12.20-12.35 (s, br, 1H).
75% With sodium hydroxide; trichlorophosphate In <i>N</i>-methyl-acetamide EXAMPLE 1
Trans-2-[5-Cyanoindol-3-yl]-1-(N,N-dimethylaminomethyl)cyclopropane
Phosphorus oxychloride (10.9 ml, 117 mmol) was added dropwise over 30 min to anhydrous dimethylformamide (50 ml) that was maintained at 10-20° C. (internal temperature).
The resulting mixture was stirred for 30 min and then chilled to 0° C.
A solution of commercially available 5-cyanoindole (15 g, 106 mmol) in anhydrous dimethylformamide (30 ml) was added over 10 min.
The ice bath was removed and the solution was allowed to warm to room temperature.
After 2 h, a very thick paste resulted.
The off-white paste was carefully quenched with ice chips.
An aqueous solution of sodium hydroxide (2.12 g NaOH/100 ml H2O) was added.
After a mild exotherm, a clear yellow solution resulted.
The solution was poured into water (~400 ml) and a fine solid immediately precipitated.
The mixture was filtered through a 600 ml glass fritted funnel of medium porosity.
The yellow filtrate was diluted with an equal volume of water and left to stand for 16 h.
A yellow precipitate was collected by vacuum filtration.
The solid was dried overnight under vacuum to afford 13.6 g (75percent yield) of (5-cyanoindol-3-yl)carboxaldehyde: 1H NMR (500 MHz, DMSO-d6) 12.58 (1 H, br s,), 10.00 (1 H, s), 8.51 (1 H, d, J=3.1 Hz), 8.46 (1 H, d, J=0.6 Hz), 7.22 (1 H, dd, J=8.6, 0.5 Hz), 7.64 (1 H, dd, J=8.5, 1.6 Hz); MS m/e 171 (M+H)+.
Reference: [1] Patent: EP997474, 2000, A1,
[2] Patent: US6180627, 2001, B2,
[3] Patent: US2003/73849, 2003, A1,
[4] Organic Process Research and Development, 2008, vol. 12, # 2, p. 168 - 177
  • 5
  • [ 15861-24-2 ]
  • [ 110-18-9 ]
  • [ 17380-18-6 ]
YieldReaction ConditionsOperation in experiment
52% 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
  • 6
  • [ 15861-24-2 ]
  • [ 68-12-2 ]
  • [ 17380-18-6 ]
YieldReaction ConditionsOperation in experiment
62% at 0 - 26℃; for 3 h; POCI3 (3.6 mL, 38.68 mmol) was added to DMF (l 6.5 mL) dropwise at 0 °C- 10 °C. The resulting mixture was stirred for 30 minutes, cooled to 0 °C, and a solution of Intermediate Z (5.0 g, 35.17 mmol) in DMF (10.0 mL) was added over15 minutes. After the addition was complete, the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with ice (25 g), poured into water (50 mL), and NaOH (1.5g) was added. The mixture was filtered, and the yellow colored filtrate was diluted with water (100 mL) and left to stand at room temperature for 20 hours. The solid was then filtered and dried to affordIntermediate AA (1.5 g, 62percent) as a yellow solid. 1H NMR (DMSO-c3/4: δ 12.59 (bs, 1H), 10.00 (s, 1H), 8.52 (s, 1 H), 8.51 (s, 1H), 7.71 (s, J = 8.29 Hz; 1H), 7.65 (d, J = 8.70 Hz; 1H). Mass (M-H): 169.1
Reference: [1] Organic Letters, 2013, vol. 15, # 17, p. 4330 - 4333
[2] Chemical Biology and Drug Design, 2011, vol. 78, # 5, p. 864 - 868
[3] Journal of Agricultural and Food Chemistry, 2013, vol. 61, # 24, p. 5696 - 5705
[4] MedChemComm, 2018, vol. 9, # 11, p. 1882 - 1890
[5] Organic Letters, 2005, vol. 7, # 13, p. 2651 - 2654
[6] Journal of Medicinal Chemistry, 2005, vol. 48, # 19, p. 6023 - 6034
[7] Patent: WO2011/47156, 2011, A1, . Location in patent: Page/Page column 57-58
[8] Farmaco, 1994, vol. 49, # 6, p. 443 - 448
[9] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 1, p. 81 - 86
[10] Journal of Medicinal Chemistry, 1997, vol. 40, # 18, p. 2843 - 2857
[11] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 6, p. 1793 - 1798
[12] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7274 - 7277
[13] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 1, p. 307 - 310
[14] Patent: EP1859798, 2015, B1, . Location in patent: Paragraph 0160
[15] Organic and Biomolecular Chemistry, 2018, vol. 16, # 36, p. 6647 - 6651
  • 7
  • [ 15861-24-2 ]
  • [ 298-12-4 ]
  • [ 17380-18-6 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 20, p. 3707 - 3710
  • 8
  • [ 15861-24-2 ]
  • [ 1196-69-6 ]
YieldReaction ConditionsOperation in experiment
55% With acetic acid In pyridine; water; ethyl acetate PREPARATION 6
Indole-5-carboxaldehyde
To a solution of 5-cyanoindole (5 g, 32.2 mmol) in pyridine (70 ml) was added acetic acid (35 ml), an aqueous solution of sodium hypophosphite (10 g in 35 ml H2 O) followed by the addition of Ra-Ni.
The resultant mixture was heated at 45° C. for 3 hours and then filtered through celite.
The filtrate was combined with water (150 ml) and ethyl acetate (150 ml).
The organic extract was separated, washed with aqueous cupric sulfate (3*1001 ml), water (2*100 ml), dried (MgSO4) and evaporated under reduced pressure to afford 5.1 g of a crude product (a beige solid).
The crude product was purified by crystallization from chloroform (40 ml) yielding 2.8 g (55percent) of the title compound as a white solid. (Helv. Chim. Acta, 51, 1616 (1968)) 1 H NMR (CDCl3) δ=6.70 (t, J=2 Hz, 1H), 7.28 (t, J= 2 Hz, 1H), 7.46 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 8.16 (s, 1H).
8.58 (bs, 1H), 9.12 (s, 1H).
Reference: [1] Patent: US5399574, 1995, A,
[2] Patent: US5409941, 1995, A,
  • 9
  • [ 15861-24-2 ]
  • [ 56-45-1 ]
  • [ 139393-02-5 ]
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 31, p. 10769 - 10776
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 38, p. 11577 - 11581[3] Angew. Chem., 2016, vol. 128, p. 11749 - 11753,5
  • 10
  • [ 15861-24-2 ]
  • [ 81881-74-5 ]
YieldReaction ConditionsOperation in experiment
100% With ammonia; hydrogen In methanol; water 5-Cyanoindole was hydrogenated over Raney Nickel in methanol with aqueous ammonia. The solution was concentrated under reduced pressure to a light yellow solid (C-(1H-indol-5-yl)-methylamine, 5.25 g, quantitative).
79% With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 45℃; for 16 h; To a stirring suspension of LiA1H4 (452 mg, 12.0 mmol) in THF (10 mL) was added asolution of 1H-indole-5-carbonitrile SM (994 mg, 7.0 mmol) in THF (8 mL) at 0 °C. The mixturewas warmed to 45 °C and stirred for 16 h. The reaction mixture was quenched with water (0.5 mL), 15percent NaOH( 0.5 mL) and then water (1.5 mL). The mixture was filtered and concentrated to obtain the residue, which was diluted with EtOAc (30 mL) and washed with water (10 mL) and then brine (10 mL). The organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the residue, which was washed with Et20 (15 mL) to afford (1H- indol-5-yl)methanamine compound 1 (790 mg, 79percent) as light yellow solid. ‘H NMR (300 MHz, DMSO-d6): 10.94 (s, 1H), 7.44 (s, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.04 (d, J 8.0 Hz, 1H), 6.34(s, 1H), 3.74 (s, 2H), 1.71 (s, 2H).
59% With hydrogen In methanol for 20 h; Cyano derivative (N.ident.C-R7) (0.3g, 1 equivalent) was dissolved in 100 ml of MeOH, then a 40 bar pression of hydrogen is applied in the presence of Ni/Raney for 20 h. The reaction mixture is filtered through celite and concentrated. The crude product was purified by flash chromatography to afford the amine. The amine (1 equivalent) was dissolved in DMF (0.4M), then the ethyl isocyanatoacetate (1 equivalent) was added in one portion and the reaction mixture was let 2h at room temperature. After the reaction was complete (TLC control), the reaction mixture was concentrated and purified by flash chromatography to afford the urea.; Example 47: Preparation of ethyl 2-(3-((indol-5-yl)methyl)ureido)acetate (F575)(47). 5-cyano-indole (0.3 g, 2.1 1 mmol) was reduced to obtain the 5- aminomethylindole (0.18g, 59percent) after purification by flash chromatography (AcOEt/MeOH 7/3 then MeOH) Rf=0.09 (MeOH). H NMR (DMSO): δ 2.40 (s, 2H), 3.78 (s, 2H), 6.38 (m, 1 H), 7.10 (d, 1 H, J = 8.3 Hz), 7.29 (m, 1 H), 7.33 (d, 1 H, J = 8.3 Hz), 7.49 (s, 1 H), 1 1 .00 (s, 1 H). The 5-aminomethylindole (57 mg, 0.39 mmol) was used to obtain urea 47 (63 mg, 66percent) after treatment of the crude product by EDP Rf=0.57 (AcOEt). H NMR (DMSO): δ 1 .21 (t, 3H, J= 7.1 Hz), 3.81 (d, 2H, J = 6.0 Hz), 4.1 1 (q, 2H, J = 7.1 Hz), 4.28 (d, 2H, J = 5.7 Hz), 6.24 (t, 1 H, J = 6.0 Hz), 6.39 (s, 1 H), 6.58 (t, 1 H, J = 5.7 Hz), 7.01 (d, 1 H, J= 8.3 Hz), 7.38 (m, 3H), 1 1 .03 (s, 1 H). HPLC method A tr= 8.37 mn (97.3percent). ESI-MS m/z: 276.2 [M + H]+.
45%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
Stage #2: With sodium hydroxide; water In tetrahydrofuran at 0℃;
Example 6; Indole-5-methanamme (4).; To an ice-cold 1.0 M solution Of LiAlH4 in THF(18 mL, 0.018 mol) was added dropwise under N2 a solution of 5-cyanoindole (16, 1.56 g, 0.011 mol) in dry THF (25 mL). After the addition was complete, the mixture was allowed to warm to room temperature and was stirred overnight. The resulting mixture was cooled in an ice bath, and excess LiAlH4 was quenched with 10percent NaOH. The product was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation to give the crude product (1.1 g), which was recrystallized from ethyl acetate/hexanes to give crystalline 5 (0.7 g, 45percent). 1H NMR (400 MHz, DMSO-^) δ 11.0 (s, IH), 7.5 (s, IH), 7.3 (d, 2H, J= 8.4 Hz), 7.0 (d, IH, J= 8.4 Hz), 6.4 (s, IH), 3.8 (s, 2H), 2-3 (br, 2H). HRMS (EI): calculated for C9H10N2 (M+): 146.0838. Found: 146.0835.
32% With ammonia; hydrogen In methanol at 20℃; To a solution of lH-indole-5-carbonitrile (1.0 g, 7.0 mmol, 1.0 eq) in NLh/MeOH (10 mL) was added Raney Ni (about 100 mg). The suspension was hydrogenated at rt overnight. The mixture was filtered. The filtered cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified via flash chromatography to afford (lH-indol-5-yl)methanamine as an off-white solid (330 mg, 32percent).

Reference: [1] Patent: US2004/204455, 2004, A1, . Location in patent: Page/Page column 18
[2] Chemistry - A European Journal, 2016, vol. 22, # 14, p. 4991 - 5002
[3] Patent: US2003/153596, 2003, A1,
[4] Patent: WO2016/44770, 2016, A1, . Location in patent: Page/Page column 584; 585
[5] Patent: WO2011/76784, 2011, A2, . Location in patent: Page/Page column 66
[6] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 5, p. 1331 - 1338
[7] Patent: WO2007/35964, 2007, A2, . Location in patent: Page/Page column 6; 13
[8] Patent: WO2015/103317, 2015, A1, . Location in patent: Page/Page column 160
[9] Journal of Medicinal Chemistry, 2005, vol. 48, # 18, p. 5823 - 5836
[10] Patent: US6180627, 2001, B2,
[11] Chemistry - A European Journal, 2008, vol. 14, # 31, p. 9491 - 9494
[12] ChemSusChem, 2017, vol. 10, # 5, p. 842 - 846
[13] Enzyme and Microbial Technology, 2018, vol. 118, p. 83 - 91
  • 11
  • [ 15861-24-2 ]
  • [ 24424-99-5 ]
  • [ 475102-10-4 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With dmap In tetrahydrofuran at 20℃; for 0.5 h;
Stage #2: for 2 h;
In a 100 mL round-bottom flask was placed 1H-INDOLE-5-CARBONITRILE (2.0 g, 14.07 MMOL) in 20 mL of anhydrous THF. To this solution was added DMAP (0.86 g, 7.03 MMOL) and the mixture was allowed to stir for 0.5 h at rt. At this point, BOC20 (3.07 g, 14.07 MMOL) was added and the reaction stirred for an additional 2 h. The reaction was then quenched with water and extracted twice with ethyl ether. The combined organic layers were washed successively with 1 N HCI, water, and brine, then dried over MGS04 and concentrated to provide 3.26 g (96percent) of the desired product as a white SOLID.APOS;H- NMR (DMSO-d6) 8 8.20-8. 14 (m, 2H), 7.83 (d, 1H), 7.70 (d, 1H), 6.80 (d, 1H), 1.63 (s, 9H).
96%
Stage #1: With dmap In tetrahydrofuran at 20℃; for 0.5 h;
Stage #2: for 2 h;
In a 100 ml round-bottom flask was placed 1W-indole-5-carbonitrile (2.0 g, 14.07mmol) in 20 ml of anhydrous THF. To this solution was added DMAP (0.86 g, 7.03mmol) and the mixture was allowed to stir for 0.5 h at rt. At this point, BocaO (3.07 g,14.07 mmol) was added and the reaction stirred for an additional 2 h. The reaction wasthen quenched with water and extracted twice with ethyl ether. The combined organiclayers were washed successively with 1N HCI, water, and brine, then dried over MgSO4and concentrated to provide 3.26 g (96percent) of the desired product as a white solid. 1H-NMR (DMSO-c/e) 5 8.20-8.14 (m, 2H), 7.83 (d, 1H), 7.70 (d, 1H), 6.80 (d, 1H), 1.63 (s,9H).
90% With dmap In acetonitrile at 20℃; for 0.5 h; [0486] tert-butyl 5-cyano-l H-indole-1 -carboxylate (INT-65) [0487] To a flask containing 5-cyanoindole (500 mg, 3.52 mmol) in CH3CN (5 mL) was added Boc20 (920 mg, 4.22 mmol) and DMAP (42 mg, 0.35 mmol) and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated, redissolved in DCM and chromatographed (EtOAc / hexanes) to provide 766 mg (90percent) of tert-butyl 5-cyano-lH- indole-l-carboxylate INT -65 as a white solid. LCMS-ESI (m/z) calculated for C14H14N20 :242.27; found 243.1 [M+H]+, tR = 3.93 min.
Reference: [1] Synthesis, 2009, # 21, p. 3617 - 3632
[2] Journal of Organic Chemistry, 2002, vol. 67, # 21, p. 7551 - 7552
[3] Patent: WO2004/43950, 2004, A1, . Location in patent: Page 134
[4] Patent: WO2005/51957, 2005, A1, . Location in patent: Page/Page column 54-55
[5] Patent: WO2011/60389, 2011, A1, . Location in patent: Page/Page column 98-99
[6] Synthesis, 2008, # 5, p. 707 - 710
[7] Synlett, 2008, # 2, p. 294 - 296
[8] Journal of Organic Chemistry, 2005, vol. 70, # 1, p. 175 - 178
[9] Journal of Organic Chemistry, 2007, vol. 72, # 14, p. 5046 - 5055
[10] Patent: US2004/242559, 2004, A1, . Location in patent: Page 18
[11] European Journal of Medicinal Chemistry, 2017, vol. 128, p. 70 - 78
  • 12
  • [ 15861-24-2 ]
  • [ 884507-17-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3651 - 3660
[2] Patent: WO2013/26914, 2013, A1,
  • 13
  • [ 15861-24-2 ]
  • [ 676273-39-5 ]
YieldReaction ConditionsOperation in experiment
95% With potassium penicillin V; sodium thiosulfate In N,N-dimethyl-formamide Example 1
Synthesis of 3-iodo-1H-indole-5-carbonitrile (V)
1H-indole-5-carbonitrile (5 g, 35.2 mmol), KOH (7.90 g, 141 mmol) and I2 (8.90 g, 35.2 mmol) are suspended in 25 mL of DMF under inert atmosphere.
The reaction is maintained under stirring in the dark for 30 min. at 10°C, and then treated with an 0.1M solution of Na2S2O3 (150 mL).
The resulting suspension is maintained under stirring for 30 min, then filtered, and the resulting solid is washed with water and dried at 50°C under vacuum to constant weight.
Product (V) (9.0 g) is obtained as a white solid with a yield of 95percent.
1H-NMR (400 MHz, CDCl3), δ: 8.78 (1H, bs); 7.80 (1H, s); 7.46-7.40 (3H, m).
Reference: [1] Patent: EP2778165, 2014, A1, . Location in patent: Page/Page column
[2] Patent: WO2012/129338, 2012, A1,
[3] Patent: US2014/275542, 2014, A1,
  • 14
  • [ 15861-24-2 ]
  • [ 1092114-59-4 ]
YieldReaction ConditionsOperation in experiment
95% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 10℃; for 0.5 h; Inert atmosphere; Darkness Example 1
Synthesis of 3-iodo-1H-indole-5-carbonitrile (V)
1H-indole-5-carbonitrile (5 g, 35.2 mmol), KOH (7.90 g, 141 mmol) and I2 (8.90 g, 35.2 mmol) are suspended in 25 mL of DMF under inert atmosphere.
The reaction is maintained under stiffing in the dark for 30 min at 10° C., and then treated with an 0.1M solution of Na2S2O3 (150 mL) The resulting suspension is maintained under stirring for 30 min, then filtered, and the resulting solid is washed with water and dried at 50° C. under vacuum to constant weight.
Product (V) (9.0 g) is obtained as a white solid with a yield of 95percent.
1H-NMR (400 MHz, CDCl3), δ: 8.78 (1H, bs); 7.80 (1H, s); 7.46-7.40 (3H, m).
94.5% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; Preparation of compound 69a: 3-iodo-l/7-indole-5-carbonitrileTo a solution of l//-indole-5-carbonitrile (lg, 7.048 mmol) in DMF (10 mL) was added KOH pellets (1.15 g, 21.14 mmol), followed by I2 (3.57 g, 14.08 mmol) portionwise. The reaction was stirred for 1 h at RT. 10percent aq sodium bisulphite solution (10 mL) was added to the mixture and an off-white solid precipitate was formed. The suspension was filtered and the solid was washed with H20 (10 mL) and dried under vacuum to give 3-iodo-lH- indole-5-carbonitrile (1.7 g, 94.5percent) as an off white solid. .H NMR (400MHz, DMSO-d6): δ 12.18 (brs, 1H), 7.78 (s, 1H), 7.75 (d, J=1.2Hz, 1H), 7.59 (dd, J=8.4, 0.4Hz, 1H), 7.52 (dd, J=8.4, 1.6Hz, 1H).
75% With iodine; sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.416667 h; 5-Cyanoindole (0.500 g, 3.52 mmol) was dissolved in DMF (25 mL), and sodium hydroxide (0.493 g, 8.79 mmol) and iodine (0.902 g, 3.55 mmol) were added thereto, then the mixture was stirred at room temperature for 25 minutes. A saturated aqueous sodium thiosulfate solution was added to the mixture, and the precipitated solid was filtered off to give 5-cyano-3-iodoindole(0.707 g, 75percent). ESI-MS: m/z 269 [M + H]+.
Reference: [1] Patent: US2014/275542, 2014, A1, . Location in patent: Paragraph 0060; 0061
[2] Patent: WO2012/129338, 2012, A1, . Location in patent: Page/Page column 192-193
[3] Patent: EP2163554, 2010, A1, . Location in patent: Page/Page column 107
[4] Organic Letters, 2013, vol. 15, # 12, p. 2982 - 2985
[5] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4031 - 4033
[6] Patent: US2004/63768, 2004, A1, . Location in patent: Page/Page column 9
[7] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 1, p. 22 - 26
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