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[ CAS No. 6146-52-7 ] {[proInfo.proName]}

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Chemical Structure| 6146-52-7
Chemical Structure| 6146-52-7
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Product Details of [ 6146-52-7 ]

CAS No. :6146-52-7 MDL No. :MFCD00005673
Formula : C8H6N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :OZFPSOBLQZPIAV-UHFFFAOYSA-N
M.W : 162.15 Pubchem ID :22523
Synonyms :

Calculated chemistry of [ 6146-52-7 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 47.12
TPSA : 61.61 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) : -6.43 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.23
Log Po/w (XLOGP3) : 1.21
Log Po/w (WLOGP) : 2.6
Log Po/w (MLOGP) : 1.12
Log Po/w (SILICOS-IT) : 0.72
Consensus Log Po/w : 1.37

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.1
Solubility : 1.3 mg/ml ; 0.00801 mol/l
Class : Soluble
Log S (Ali) : -2.1
Solubility : 1.29 mg/ml ; 0.00793 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.13
Solubility : 0.12 mg/ml ; 0.000738 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.48

Safety of [ 6146-52-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P501-P202-P201-P280-P308+P313-P405 UN#:N/A
Hazard Statements:H341 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 6146-52-7 ]

* 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 [ 6146-52-7 ]
  • Downstream synthetic route of [ 6146-52-7 ]

[ 6146-52-7 ] Synthesis Path-Upstream   1~40

  • 1
  • [ 6146-52-7 ]
  • [ 5192-03-0 ]
YieldReaction ConditionsOperation in experiment
98% With silver tetrafluoroborate; 4,4'-Dimethoxy-2,2'-bipyridin; potassium <i>tert</i>-butylate; hydrogen In 1,4-dioxane at 80℃; for 24 h; Autoclave In Example 1, the m-nitroacetophenone used was replaced with an equimolar 5-nitroindole, and at a hydrogen pressure of4.0 MPa for 24 hours at 80 ° C. The other procedure was the same as in Example 1 to give 5-aminoindole in a yield of 98percent, _: A solution of 16.44 mg (0.04 mmol) 4,4'-dimethoxy-2,2'-bipyridine silver 11.22 mg (0.1 mmol) of potassuim t-butoxide and 1 mL of 1,4-dioxane were charged into an autoclave. After stirring, 165.15 mg (1 mmol) of m-nitroacetophenone was added and the mixture was stirred at 80 °C. The reaction was carried out for 8 hours. After the reaction has finishedm the reaction solution was extracted with water and dichloromethane to collect the organic phase. Then, the organic phase was dried over anhydrous Na2SO4, suction filtered, rotary evaporated and chromatographed to give a yellow solid 3-acetanilide. Yield 96 percent.
96% With hydrogen In ethanol; ethyl acetate To reduce a given model compound (5-nitroindol) in accordance with the above reaction scheme (to 5-aminoindol), the reservoir 104 of the hydrogenation apparatus 100 was filled with, as a sample solution, a stock solution of a 1:1 mixture of EtOAc:EtOH containing 5-nitroindol in a concentration of 0.05 mol/dm3. At the same time, a catalyst of 10percent by weight bone black palladium (Pd) or Raney nickel was arranged within the reactor 110 as the catalyst packing. After this, a flow rate of 0.1 ml/s was set within the apparatus by means of the feed pump 102, while a pressure of 30 bar was generated in the flow path by means of the pressure-adjusting unit 112. During the operation of the apparatus these values were continuously maintained. The produced hydrogenate, i.e. the 5-aminoindol was collected in the product receptacle 114, and then was subjected to an analytical assay (HPLC UV, λ=254 nm). As a result of the analysis, we concluded that the collected hydrogenate was of the purity of 99.9percent, and the yield of the reaction was about 96percent.
94% With sodium tetrahydroborate In methanol; water at 0 - 50℃; for 2 h; General procedure: A mixture of nitroarene (1 mmol), SS-Pd (2 molpercent Pd) and sodium borohydride (3 mmol) were taken in a 25 ml round bottomed flask. 3 ml of MeOH:H2O (3:7) was added to the mixture by a syringe at 0 oC in stirring condition. After 10 minutes the reaction mixture was heated to 50 oC. Progress of the reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Na2SO4. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines.
92.5% With hydrogen In ethanol for 3 h; A mixture of 5-nitro-1H-indole (11 g, 67.9 mmol) and Pd/C (5percent; 1 g), dissolved in ethanol (50 mL), was hydrogenated for 3 h at 40 psi. The reaction mixture was filtered and the excess of ethanol was evaporated under reduced pressure. Solid product was recrystallized from hexane to obtain the pure compound 5-aminoindole (55-1). Yield: 92.5percent. 1H NMR (500 MHz, CDCI3): δ 7.96 (br, 1 H), 7.20 (d, 1 H), 7.13 (s, 1 H), 6.95 (s, 1 H), 6.67 (dd, 1 H), 6.37 (s, 1 H), 3.50 (s, 2 H). MS (ESI) mJz 133.0 (M + H)+.
90% With sodium tetrahydroborate; PdCu/graphene (2 mol % Pd) In ethanol; water at 0 - 50℃; General procedure: A mixture of nitroarene (1 mmol), PdCu/graphene (6 mg) and sodium borohydride (2mmol) were taken in a 25 mL reaction tube. 3 mL of EtOH:H2O (1:2 in volume ratio) was added by a syringe at 0°C. After 10 min the reaction mixture was placed in an oil bath at 50°C. The reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Mg2SO4. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60–120 mesh) afforded desired corresponding amines.
81% With hydrazine In ethanol for 2 h; Reflux 25 mL of hydrazine (98-100percent) are added slowly to a mixture of 25.0 g of 5-nitroindole, 1.2 g of 10percent palladium on carbon and 200 mL of absolute ethanol. After the addition, the resulting reaction mixture is then taken to reflux for 2 hours. The catalyst is eliminated by filtration and the filtrate is evaporated in order to produce a solid yellow residue. The crystals are washed with 200 ml of water and they are dried under vacuum in order to produce 16.5 g (81percent) of 5-aminoindole. Melting point: 131-134° C.
79% With hydrazine hydrate In ethanol at 80℃; for 1 h; Inert atmosphere General procedure: Hydrazine hydrate was chosen as the hydrogen donor for the low emission of pollutants. In a typical procedure, hydrazine hydrate (4 equiv) was added into the reactor which containing fresh prepared catalyst as described above. Then the reactor was put into a preheated oil bath with a stirring speed of 500 rpm, and the substrate (1 mmol)dissolved in 1 mL ethanol was added drop-wisely under argon. The reactions were monitored by TLC. After the reaction, the reaction mixture was vacuum filtered through a pad of silica on a glass-fritted funnel and an additional 15 mL of ethyl acetate (5 mL portions) was used to rinse the product from the silica, the filtrate was concentrated in vacuum and analyzed by GC. Products were purified by column chromatography and identified by 1H NMR and 13C NMR.
55% With ammonium formate In tetrahydrofuran; methanol REFERENCE EXAMPLE 1
Preparation of (1H-indole-5-yl)-amine
5-nitroindole (1.0 g, 6.17 mmol) was dissolved in methanol (10 ml) and anhydrous tetrahydrofuran (10 ml) at room temperature and then, palladium/carbon (10percent) of a catalystic amount and ammonium formate (2.0 g, 31.7 mmol) were added to be stirred slowly at room temperature for 30 minutes.
After completing the reaction, the reacting solution was filtered through celite, washed with methanol, concentrated under reduced pressure and then, dropped a silica gel short column.
Afterward, the residue was concentrated again under reduced pressure and triturated with isooctane.
As a result, the present compound (0.45 g, productive yield 55percent) was obtained as a solid phase.
1H-NMR (400 MHz, CDCl3) δ2.55 (br s, 2H), 6.35 (s, 1H), 6.65 (d, J=8 Hz, 1H), 6.95 (s, 1H), 7.10-7.15 (m, 1H), 7.20 (d, J=8 Hz, 1H), 7.95 (br s, 1H) melting point: 126° C.
53% With palladium 10% on activated carbon; hydrogen In ethanol for 2.5 h; General procedure: General procedure (9): Nitroindole derivative (1 equiv) was dissolved in ethanol (30 ml_ for 20.40 mmol of starting material) and 10percent palladium on carbon (10 mmolpercent) was added. The reaction flask was shaken under hydrogen at 30 psi using the Parr Shaker Hydrogenation Apparatus for 2.5 h. The reaction was filtered over celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by silica gel flash column chromatography to afford the aminoindole product. Intermediate 16 1/-/-indol-5-amine Intermediate 16 (2.7 g, 20.4 mmol) was prepared as a black solid from 5-nitro-1 /-/-indole (6.3 g, 38.9 mmol, 1 equiv) according to general procedure (9) using 1 :1 hexane/ethyl acetate as the eluent for flash silica gel column chromatography. Yield: 53percent. 1H NMR (400 MHz, CDCI3) δ: 7.96 (bs, 1 H), 7.22 - 7.17 (m, 1 H), 7.13 (t, J = 2.8 Hz, 1 H), 6.97 - 6.94 (m, 1 H), 6.67 (dd, J = 8.5, 2.2 Hz, 1 H), 6.39 - 6.37 (m, 1 H), 3.49 (s, 2H).
53% With palladium 10% on activated carbon; hydrogen In ethanol for 2.5 h; 5-nitro-1H-indole (6.3 g, 38.9 mmol, 1 equiv) was dissolved in ethanol (30 mL). 10percent palladium on carbon (630 mg, 10 mmolpercent) was added. The reaction flask was shaken under hydrogen at 30 psi using the Parr Shaker Hydrogenation Apparatus for 2.5 h. The reaction was filtered over celite and washed with ethyl acetate. The filtrate was evaporated, concentrated in vacuo and purified by silica gel flash column chromatography (1:1 hexane/ethyl acetate) to afford intermediate 16 as a black solid (2.7 g, 20.4 mmol). Yield: 53percent. 1H NMR (400 MHz, CDCl3) δ: 7.96 (bs, 1H), 7.22-7.17 (m, 1H), 7.13 (t, J = 2.8 Hz, 1H), 6.97-6.94 (m, 1H), 6.67 (dd, J = 8.5, 2.2 Hz, 1H), 6.39-6.37 (m, 1H), 3.49 (s, 2H).
51%
Stage #1: With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5 h;
Stage #2: With sodium hydrogencarbonate In water
General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
152.2 mg With sodium tetrahydroborate; PdCu/graphene (2 mol % Pd) In ethanol; water at 0℃; for 1.5 h; Heating General procedure: A mixture of nitroarene (1 mmol), PdCu/graphene (6 mg) and sodium borohydride (2 mmol) were taken in a 25 mL reaction tube. 3 mL of EtOH:H2O (1:2 in volume ratio) was added by a syringe at 0 °C. After 10 min the reaction mixture was placed in an oil bath at 50 C. The reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried ove ranhydrous Mg2SO4. Evaporation of the combined organic layer andfollowed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines.
80.6 %Chromat. With ammonium formate; cetyltrimethylammonim bromide In water at 130℃; for 6 h; Inert atmosphere General procedure: For the catalytic reactions, typically, 0.5 mmol nitroarene,2.5 mL solvent, 189 mg ammonium formate (3.0 mmol), and catalyst (20 mg) were added to a 15 mL pressure bottle reactor (maximum pressure 1.0 MPa, the typical reaction pressure wasless than 0.4 MPa) with magnetic stirring. The atmosphere in the reactor was then replaced with Ar gas three times and tightly sealed. The reactor was placed in an oil bath preheated to the desired temperature. After the set reaction time, the reactor was quenched with cold water and the reaction mixture was diluted with 7.5 mL ethanol. The ethanol solution was analyzed by GC and GC‐MS.

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  • [ 6146-52-7 ]
  • [ 20876-36-2 ]
YieldReaction ConditionsOperation in experiment
82% With zinc In water; acetic acid; ethyl acetate; <i>tert</i>-butyl alcohol EXAMPLE 6
Preparation of FCE 28901
To a stirred solution of 5-nitroindole (4 g, 24.6 mmol) in 200 ml of t-Butanol was added, portionwise, pirydinium bromide perbromide (30 g, 93 mmol) over a period of 0.5 h.
The reaction mixture was stirred at room temperature overnight, then t-Butanol was removed and the resulting residue dissolved in ethyl acetate/water (500/500 ml).
The organic layer was separated and the aqueous layer was extracted with 300 ml of ethyl acetate.
The organic extracts were washed with water, dried over sodium sulphate anhydrous and concentrated in vacuo to give 8.5 g of a less polar compound that was recrystallized from ethyl acetate to give 7.5 g of dibromoderivative.
Hydrogenation of this compound with 10 equivalents of zinc dust in 80 ml of acetic acid at room temperature for 3 h gave 5-amino oxindole in good yields (3 g, 82percent yield).
EI-MS: m/z 148 (100, [M]+); 120 (56, [M-CO]+); 119 (94, [M-CO--H]+); 105 (22, [M-HNCO]+)
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  • [ 32692-19-6 ]
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  • 9
  • [ 6146-52-7 ]
  • [ 20870-79-5 ]
YieldReaction ConditionsOperation in experiment
81% With 1-fluoro-1,2-phenyliodohydrin-3-(1H)-one In 1,4-dioxane; water at 140℃; for 5 h; Add 0.4 mL of 1,4-dioxane to a 50 mL reaction tube at room temperature.Add 2mL more water,Stir and mix.Weighing 1-fluoro-1,2-phenyliodohydrin-3-(1H)-one (175 mg, 0.66 mmol) was added to the reaction tube and stirred for 1 min.After the reaction tube was placed in a 140 ° C oil bath,Add 5-nitroindole (97 mg, 0.6 mmol),A built-in condenser was added and reacted in a 140 ° C oil bath for 5 hours.The TLC dot plate shows that the raw material reaction is complete,The reaction tube was taken out of the oil bath, cooled to room temperature, and quenched by adding 10 mL of saturated sodium hydrogencarbonate.It was extracted with ethyl acetate (20 mL).The organic layer is concentrated by steaming,The pink solid 5-nitro-substituted 2-indanone 86 mg was obtained by column chromatography.The yield was 81percent.
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  • [ 611-09-6 ]
YieldReaction ConditionsOperation in experiment
80% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; oxygen In acetonitrile at 20℃; for 8 h; General procedure: An oven-dried flask was charged with stir bar, oxindole (0.5 mmol), PIDA (0.25 mmol) in dry acetonitrile (4.0 mL). Then to the reaction mixture TEMPO (0.5 mmol) was added in presence of air and the mixture was stirred at room temperature until complete conversion takes place as indicated by TLC analysis. The resulting reaction mixture was extracted with ethyl acetate (3 10 mL). The combined organics were dried with Na2SO4 and dried under vacuum to afford crude solid. Then the crude product was purified by column chromatography on silica gel.
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  • [ 4693-02-1 ]
Reference: [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 43, p. 7455 - 7457
  • 12
  • [ 6146-52-7 ]
  • [ 140-29-4 ]
  • [ 7147-14-0 ]
YieldReaction ConditionsOperation in experiment
93% With copper(l) iodide In N,N-dimethyl-formamide at 100℃; for 34 h; General procedure: A mixture of CuI (0.6 mmol), indoles (0.5 mmol) and benzyl cyanide (0.6 mmol) in DMF (3.0 mL) was stirred under air at 100 °C for 34 h and then cooled to room temperature. After the reaction mixture was quenched with 10 mL of water, it was extracted with DCM (3×10 mL). The combined organic layers were washed with the saturated aqueous solution of sodium chloride and dried over MgSO4. The solution was concentrated under reduced pressure and purified by column chromatography to afford 3-cyanoindoles.
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  • [ 7147-14-0 ]
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  • [ 7147-14-0 ]
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  • 15
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  • [ 7147-14-0 ]
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  • [ 7145-71-3 ]
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[2] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 344 - 367
  • 17
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  • [ 6958-37-8 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: at 0℃; for 24 h; Inert atmosphere
Stage #2: With potassium hydroxide In water for 2 h; Reflux; Enzymatic reaction
Stage #3: With dihydrogen peroxide In water for 4 h;
5-Nitroindole (lg, 6.2 mmol) was suspended in diethyl ether and oxalyl chloride (4.3 ml , 49.4 mmol) was added under nitrogen atmosphere at 0°C. The resulting reaction mixture was stirred at 0 °C for 24 h and the resulting precipitate was filtered washed with cold diethyl ether and dried. After drying mass was further dissolved in thesolution of potassium hydroxide (1.63 g, 29 mmol) in water (40 ml) and refluxed for 2 hours. The reaction mixture was ice cooled, acidified with 12 N HC1 to pH 1. The obtained precipitated was filtered, washed with iN HC1 and dried. This precipitate was further dissolved in 10 percent hydrogen peroxide solution (75 ml ), refluxed for 4 h and cooled to room temperature. The obtained precipitated was filtered, washed with cold water and dried to obtain A as a greenish yellow solid(750 mg, 61percent). 1H NMR (DMSO-d6): ö 12.49-12.46 (2H, NH & OH), 8.91 (d, 1H,JAB= 2.0 Hz, ArH), 8.29 (d, 1H,JAB = 2.0 Hz, ArH), 8.10 (dd, 1H,JAB= 9.0 Hz,Jm= 2.5 Hz,ArH), 7.68 (d, 1H,JAB= 9.0 Hz,ArH); ESI-MS (mlz): 206.93 (M+H).
Reference: [1] Patent: WO2017/17631, 2017, A2, . Location in patent: Paragraph 00363
  • 18
  • [ 6146-52-7 ]
  • [ 6958-37-8 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 2006, vol. 71, # 6, p. 899 - 911
[2] Patent: US4940703, 1990, A,
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9875 - 9890
[4] Patent: WO2017/35351, 2017, A1,
[5] Russian Journal of General Chemistry, 2017, vol. 87, # 12, p. 3006 - 3016
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  • [ 6146-52-7 ]
  • [ 68-12-2 ]
  • [ 6958-37-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1019 - 1031
  • 20
  • [ 6146-52-7 ]
  • [ 74-88-4 ]
  • [ 29906-67-0 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h;
Stage #2: at 20℃;
Step F: Synthesis of l-methyl-5-nitro-lH-indole as an intermediate; [0099] To a mixture of 5-nitro-lH-indole (5.0 g, 30.8 mmol) in λ/,λf-dimethylformamide (100.0 mL) was added sodium hydride (60percent in mineral oil, 1.35 g, 33.9 mmol), and the mixture stirred for 1 h at room temperature. After this time, iodomethane (2.11 mL, 33.9 mmol) was added, and the mixture was stirred at room temperature overnight. After this time, saturated aqueous ammonium chloride (100 mL) was added and the organics extracted with ethyl acetate (150 mL). The organics were then washed with 5percent aqueous lithium chloride (200 mL), water (200 mL) and brine (1000 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford l-methyl-5-nitro-lH-indole (5.42 g, 100percent) as an orange/brown solid: 1H NMR (500 MHz, CDCl3) δ 8.59 (d, J= 2.0 Hz, IH), 8.13 (dd, J = 2.0, 9.0 Hz, IH), 7.34 (d, J= 9.0 Hz, IH), 7.20 (d, J= 3.0 Hz, IH), 6.67 (dd, J= 0.5, 1.0, 3.0, 3.5 Hz, IH), 3.86 (s, 3H).
100%
Stage #1: With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 1 h;
Stage #2: at 20℃;
Dissolve A1 (10.0 g, 61.7 mmol) in 100 ml of N,N-dimethylformamide.A tetrahydrofuran suspension of NaH (2.7 g, 112.5 mmol) was slowly added dropwise and reacted for 1 hour at room temperature. 4.3 ml of methyl iodide was added and the reaction was stirred overnight at room temperature. After the reaction was completed, it was washed with 1 L of saturated ammonium chloride solution and extracted with 500 ml of ethyl acetate to obtain an organic layer. Then, 400 ml of a 5percent lithium chloride solution, 1 L of water, and 1 L of brine are successively washed, and the organic layer is added with anhydrous magnesium sulfate. After drying overnight, the solvent was removed to obtain 10.9 g of A2. The yield of this step was 100percent, which was completely converted into the target product.
92% With potassium hydroxide In acetone at 0℃; for 10 h; Heating / reflux To a solution of 5 -nitro-1 H-indole (2.Og, 12.3mmol) in acetone (20ml), powdered potassium hydroxide (3.4g, 60.7mmol, 5eq) was added followed by the addition methyl iodide (2.6 Ig, 18.5mmol, 1.5eq) at O0C. The reaction mixture was heated to reflux for 10 hr. The solvent was evaporated and water was added. The compound was extracted with ethyl acetate, dried over anhydrous sodium sulphate, filtered and the organic layer was concentrated to dryness to yield l-methyl-5 -nitro-1 H-indole (2.Og, 92percent). The crude compound was used in the next stage without purification.
47.5% With potassium carbonate In acetonitrile at 80℃; The 5-nitroindole (972mg, 6mmol), K2CO3 (1.66g, 7.2mmol) was dissolved in acetonitrile (20ml), a 80 °C was heated at reflux for several hours, until TLC monitored the reaction. After rotary evaporation and then, solid was dissolved in ethyl acetate, added saturated NH 4Cl solution and extracted. The organic layers were combined, spin crude done. Finally, the product was purified by column to give the intermediate 1-methyl-5-nitro-indole -1H- 769mg. Yield 47.5percent.

Reference: [1] Patent: WO2009/42907, 2009, A1, . Location in patent: Page/Page column 36
[2] Patent: CN107163029, 2017, A, . Location in patent: Paragraph 0049; 0050; 0051; 0052
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5509 - 5513
[4] Synthetic Communications, 1998, vol. 28, # 1, p. 147 - 157
[5] Organic Letters, 2004, vol. 6, # 17, p. 2897 - 2900
[6] Journal of the American Chemical Society, 2005, vol. 127, # 22, p. 8050 - 8057
[7] Patent: WO2006/123145, 2006, A1, . Location in patent: Page/Page column 48
[8] Patent: WO2018/171575, 2018, A1, . Location in patent: Page/Page column 23; 33; 35; 67
[9] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 10, p. 3531 - 3541
[10] Collection of Czechoslovak Chemical Communications, 2006, vol. 71, # 5, p. 679 - 690
[11] Organic Letters, 2013, vol. 15, # 1, p. 112 - 115
[12] Chemistry - A European Journal, 2016, vol. 22, # 13, p. 4400 - 4404
[13] Patent: CN104163815, 2017, B, . Location in patent: Paragraph 0065-0067
[14] Journal of Organic Chemistry, 1986, vol. 51, # 19, p. 3694 - 3696
[15] Journal of Medicinal Chemistry, 1993, vol. 36, # 8, p. 1104 - 1107
[16] Journal of Medicinal Chemistry, 1992, vol. 35, # 1, p. 177 - 184
[17] Organic Letters, 2010, vol. 12, # 21, p. 4956 - 4959
[18] Patent: US2011/190299, 2011, A1, . Location in patent: Page/Page column 22-23
[19] Chemical Communications, 2014, vol. 50, # 81, p. 12181 - 12184
[20] Organic and Biomolecular Chemistry, 2017, vol. 15, # 28, p. 5904 - 5907
[21] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1202 - 1213
[22] European Journal of Medicinal Chemistry, 2018, vol. 160, p. 120 - 132
[23] Patent: US6242470, 2001, B1,
  • 21
  • [ 6146-52-7 ]
  • [ 616-38-6 ]
  • [ 29906-67-0 ]
  • [ 91482-63-2 ]
YieldReaction ConditionsOperation in experiment
97.1% With potassium carbonate In n-heptane; ethyl acetate; N,N-dimethyl-formamide Example 14
Synthesis of 1-methyl-5-nitroindole.
A 500 mL, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with 5-nitroindole (20.0 g, 12.3 mmol), potassium carbonate (4.0 g, 29 mmol), N,N-dimethylformamide (80 mL) and dimethyl carbonate (22 mL, 26.14 mmol).
The resulting mixture was heated to reflux.
The reaction was monitored by HPLC or TLC (solvent system: 30percent ethyl acetate in heptane).
An analysis of the reaction mixture after 3 h at reflux, by the above methods, failed to detect any remaining 5-nitroindole.
The reaction mixture was then cooled to 10+-5° C. and diluted with water (160 mL) which resulted in the formation of a yellow precipitate.
After the mixture was stirred at room temperature for 2 h, the solid was collected by filtration, then was washed with water (100 mL) and dried under high vacuum at 60-65° C. for 24 h to give 1-methyl-4-nitroindole (21.1 g, 97.1percent) as a yellow solid.
Reference: [1] Patent: US6326501, 2001, B1,
  • 22
  • [ 6146-52-7 ]
  • [ 77-78-1 ]
  • [ 29906-67-0 ]
Reference: [1] Organic Process Research and Development, 2009, vol. 13, # 1, p. 67 - 72
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 13, p. 5758 - 5764
[3] Patent: US2009/149662, 2009, A1, . Location in patent: Page/Page column 8-9
  • 23
  • [ 6146-52-7 ]
  • [ 616-38-6 ]
  • [ 29906-67-0 ]
Reference: [1] Organic Process Research and Development, 2001, vol. 5, # 6, p. 604 - 608
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1461 - 1464
[3] Journal of Organic Chemistry, 2003, vol. 68, # 5, p. 1954 - 1957
  • 24
  • [ 6146-52-7 ]
  • [ 68-12-2 ]
  • [ 6625-96-3 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: at -20 - 20℃; for 0.5 h;
Stage #2: at -20 - 20℃; for 1 h;
Stage #3: With sodium hydroxide In water; N,N-dimethyl-formamideHeating / reflux
POCl3 (0.31 ml, 3.39 mmol, 1.1 eq) was slowly dropped, under argon atmosphere and vigorous stirring, into dry DMF (2 ml) and then cooled at -20 °C. After stirring for 30 min. at room temp., the solution was cooled at -20 °C, and 5-nitro indole (500 mg, 3.08 mol, 1 eq) in 0.5 ml of dry DMF was slowly added. The yellow solution was then stirred at room temperature for 1 h. A pale-yellow compound precipitated. The mixture was diluted with DMF, and then an equal volume of icy water was added. Aqueous NaOH (50percent v/v) was then added until pH 9 was reached and the obtained red solution was refluxed, and then left overnight at 4 °C. The obtained crystals were filtered, washed with cool water and dried. Crystallization (EtOH-H2O) afforded 574 mg of the title compound XV. Yield= 98 percent. 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.69 (d, J=9.0 Hz, 1 H) 8.12 (dd, J=2.3 Hz, 1 H) 8.54 (s, 1 H) 8.91 (d, 1 H) 9.99 (s, 1 H).
98% at 0 - 20℃; for 1.5 h; POCl3 at 0 °C(9.2 ml, 98.5 mmol) was added dropwise to DMF (9.5 ml, 123.1 mmol). After stirring for 0.5 h, 5-nitro-1H-indole (compound 1, 2.0 g, 12.3 mmol) was added to the reaction solution. Then react at room temperature for 1.5 h.The reaction was then poured into a large volume of ice water and adjusted to pH 7 with 6N NaOH, extracted with ethyl acetate (x3), and concentrated to give 2.34 g of a gray solid in 98percent yield with a purity of 95.2percent.
Reference: [1] Patent: EP2003129, 2008, A1, . Location in patent: Page/Page column 16
[2] Patent: CN107915726, 2018, A, . Location in patent: Paragraph 0047-0050
[3] Organic Letters, 2008, vol. 10, # 12, p. 2601 - 2604
[4] Organic Letters, 2014, vol. 16, # 4, p. 1268 - 1268
[5] Angewandte Chemie - International Edition, 2010, vol. 49, # 33, p. 5721 - 5725
[6] Journal of the American Chemical Society, 2013, vol. 135, # 26, p. 9820 - 9828
[7] Chemical Biology and Drug Design, 2011, vol. 78, # 5, p. 864 - 868
[8] Journal of Agricultural and Food Chemistry, 2013, vol. 61, # 24, p. 5696 - 5705
[9] Chemistry - A European Journal, 2016, vol. 22, # 2, p. 716 - 723
[10] Tetrahedron Letters, 2009, vol. 50, # 1, p. 75 - 76
[11] Farmaco, 1994, vol. 49, # 6, p. 443 - 448
[12] Organic Letters, 2009, vol. 11, # 22, p. 5214 - 5217
[13] Tetrahedron Letters, 2012, vol. 53, # 17, p. 2222 - 2225
[14] MedChemComm, 2013, vol. 4, # 1, p. 228 - 232
[15] Chemistry - A European Journal, 2014, vol. 20, # 24, p. 7492 - 7500
[16] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 666 - 680
[17] Patent: CN107445944, 2017, A, . Location in patent: Paragraph 0130; 0131
  • 25
  • [ 110-18-9 ]
  • [ 6146-52-7 ]
  • [ 6625-96-3 ]
YieldReaction ConditionsOperation in experiment
40% 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
  • 26
  • [ 100-97-0 ]
  • [ 6146-52-7 ]
  • [ 6625-96-3 ]
YieldReaction ConditionsOperation in experiment
57% With iodine; oxygen; pyrographite In N,N-dimethyl-formamide at 120℃; for 19 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.
56% With aluminum (III) chloride In N,N-dimethyl-formamide at 120℃; for 17 h; General procedure: A method for synthesizing compound III-1 wherein R1, R2 and R3 are simultaneously hydrogen in the formula III, the method comprising the steps of:(1) Add to a 50 mL round bottom flask1.0mmol indole(In the formula I, R1, R2, and R3 are both hydrogen) and1.0 mmol (0.140 g) of hexamethylenetetramine, then 2 mL of N,N-dimethylformamide (DMF), stirred in a magnetic stirrer to dissolve the solid, followed by the addition of 0.05 mmol (0.012 g) of crystalline trichloride Aluminum, connected to a reflux condenser, heated at 120 ° C, the reaction progress was monitored by TLC, and the reaction was cooled to room temperature after 1 h to prepare a suspension;(2) The suspension prepared in the step (1) is suction filtered with a funnel padded with diatomaceous earth.The filter cake was washed well with ethyl acetate, suction filtered, and the above operation was repeated until the filtrate had no product, and all the filtrates were combined.Dilute with 15 mL of saturated saline solution, disperse and separate the layers, and the aqueous layer was further extracted with ethyl acetate three times.Each time 10 mL, the ethyl acetate layer was combined and washed with 10 mL of 2 mol/L diluted hydrochloric acid.Wash with 10 mL of saturated sodium bicarbonate solution, and finally wash with 10 mL of saturated brine.The washed ethyl acetate layer was dried over anhydrous sodium sulfate, and after drying, the desiccant was filtered off.Then use a rotary evaporator to recover the solvent to concentrate the product, and finally,The residue is subjected to silica gel column chromatography using a mixture of n-hexane-ethyl acetate (V/V = 2:1) as an eluent to obtain a purified product.The mass of the compound III-indole-3-carbaldehyde is 0.137g,The product yield was 94percent.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 30, p. 2877 - 2880
[2] Patent: CN108329249, 2018, A, . Location in patent: Paragraph 0041-0044; 0126-0129
  • 27
  • [ 50-00-0 ]
  • [ 6146-52-7 ]
  • [ 6625-96-3 ]
YieldReaction ConditionsOperation in experiment
57% With iron(III) chloride; ammonia In water; N,N-dimethyl-formamide at 130℃; for 16 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
  • 28
  • [ 6146-52-7 ]
  • [ 93-61-8 ]
  • [ 6625-96-3 ]
YieldReaction ConditionsOperation in experiment
80% With trichlorophosphate In ethyl acetate; 1,2-dichloro-ethane; benzene EXAMPLE 4
5-Nitro-3-indolealdehyde. [II, n=0, R2 =5-NO2, R3 =H]
A mixture of N-methylformanilide (176 mg, 1.3 mmol) and phosphorous oxychloride (199 mg, 1.3 mmol) is stirred for 15 min at 20°-25° C. under nitrogen. then a solution of 5-nitroindole (162 mg, 1 mmol) in 1,2-dichloroethane (5 ml) is added and the mixture heated to reflux for 3 h.
After cooling the mixture is poured onto iced water, the precipitate filtered off and washed with water.
Thereupon the residue is chromatographed over silica gel using benzene/ethyl acetate as eluant.
Thus pure title compound is obtained in 80percent yield (152 mg).
C9 H6 N2 O3 requires: C 56.85 H 3.18 N 14.73 found: C 56.79 H 3.01 N 14.51 MS m/z: 190 IR cm-1 (KBr): 3140, 3090 (NH), 1650 (CO), 1511, 1345 (NO2)
80% With trichlorophosphate In ethyl acetate; 1,2-dichloro-ethane; benzene EXAMPLE 6
5-nitro-3-indolealdehyde
A mixture of N-methylformanilide (1.76 g, 0.013 mol) and phosphorous oxychloride (1.99 g, 0.013 mol) was stirred for 15 min at 20°-25° C. under nitrogen.
Then a solution of 5-nitroindole (1.62 g, 0.01 mol) in 1,2-dichloroethane (50 ml) was added and the mixture heated to reflux for 3 h.
After cooling the mixture was poured onto iced water, the precipitate filtered off and washed with water.
Thereupon the residue was chromatographed over silica gel using benzene/ethylacetate as eluant.
Thus pure title compound was obtained in 80percent yield (1.52 g).
C9 H6 N2 O3 calculated: C 56.85 H 3.18 N 14.73 found: C 56.79 H,3.01 N 14.51
MS m/z 190.
IR cm-1: 3140, 3090 (NH), 1650 (CO), 1511, 1345 (NO2).
Reference: [1] Patent: US5409949, 1995, A,
[2] Patent: US5652250, 1997, A,
  • 29
  • [ 6146-52-7 ]
  • [ 298-12-4 ]
  • [ 6625-96-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 20, p. 3707 - 3710
  • 30
  • [ 6146-52-7 ]
  • [ 107753-78-6 ]
Reference: [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1781 - 1790
[2] Organic Process Research and Development, 2004, vol. 8, # 5, p. 808 - 813
  • 31
  • [ 6146-52-7 ]
  • [ 525593-33-3 ]
YieldReaction ConditionsOperation in experiment
83% With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In 1,4-dioxane at 10℃; General procedure: DBDMH (157 mg, 0.55 mmol) was added in five potion to a solution ofindoles (1.0 mmol) in dioxane at 10 °C over two minutes with stir, and the resulting solution was stirred for 5to 10 minutes. TLC indicate that the reaction is completed. The reactionsolution was poured into the saturated NaHCO3 solution (10 mL), themixtures was extracted by ethyl acetate (15 mL*2). The organic phase was dried over Na2SO4,filtered, concentrated under reduced pressure. The residue was then purified byflash chromatography on 200~300 mesh silica gel to provide the correspondingproduct 2.
74% With pyridinium hydrobromide perbromide In pyridine at -4 - 0℃; for 0.0833333 h; Step A: To a solution of 5-nitroindole (5.00 g, 30.8 mmol) in pyridine (200 rnL) at -40C was added a solution of pyridinium bromide perbromide (10.99 g, 34.3 mmol) in pyridine (200 mL) dropwise under nitrogen with stirring. After complete addition, the reaction mixture was stirred for 5 min at O0C. The reaction mixture was diluted in O0C water (200 mL) and extracted with 200 mL OfEt2O. The organic layer was washed with 6 M HCl (300 mL), 5percent NaHCO3 (300 mL), and brine (300 mL). The organic phase was dried over MgSO4 and solvent was removed to give 3-bromo-5-nitroindole as a yellow powder, 80percent pure with 20percent 5-nitroindole (6.80 g, 74percentyield).
67% at -10℃; for 0.166667 h; To a solution of 5-nitro-indole (200 mg, 1.2 mmol) in pyridine (5 mL) was added Py.HBr3 (474 mg, 1.4 mmol) at -10° C. and mixture was stirred for 10 min.
Then reaction mixture was quenched by addition of water at 0° C. and then the reaction mixture was extracted with diethyl ether.
The organic layer was washed successively with 6N HCl (20 mL), 5percent NaHCO3 (20 mL) followed by brine.
The combined organic layers were dried (Na2SO4), filtered and concentrated to obtain the title compound (200 mg, 67percent) as yellow colored solid. 1H NMR (400 MHz, CDCl3): δ 8.58-8.57 (m, 2H), 8.16 (dd, J=2.0, 8.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.8 Hz, 1H). LCMS: m/e 240.80 [M+H]+
Reference: [1] Tetrahedron Letters, 2003, vol. 44, # 20, p. 3927 - 3930
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 17, p. 5965 - 5980
[3] RSC Advances, 2016, vol. 6, # 93, p. 90031 - 90034
[4] Tetrahedron Letters, 2015, vol. 56, # 9, p. 1096 - 1098
[5] Patent: WO2006/19831, 2006, A1, . Location in patent: Page/Page column 415
[6] Patent: US2016/46597, 2016, A1, . Location in patent: Paragraph 0254
[7] New Journal of Chemistry, 2018, vol. 42, # 23, p. 18889 - 18893
[8] Russian Journal of Bioorganic Chemistry, 2013, vol. 39, # 2, p. 211 - 214
  • 32
  • [ 6146-52-7 ]
  • [ 685-87-0 ]
  • [ 525593-33-3 ]
YieldReaction ConditionsOperation in experiment
45% With tris(bipyridine)ruthenium(II) dichloride hexahydrate; N,N-diphenyl-4-methoxyaniline In N,N-dimethyl-formamide at 20℃; for 48 h; Inert atmosphere; Irradiation General procedure: An oven dried 10 mL round bottom flask was equipped with a rubber septum and magnetic bar and was charged with the heteroaromatic substrate (0.5 mmol, 1.0 equiv), tris(2,2-bipyridyl)ruthenium(II) chloride hexahydrate (5.0 μmol, 3.70 mg, 1.0 mol percent), 4-methoxytriphenylamine (1.0 mmol, 0.274 g, 2.0 equiv), diethyl bromomalonate (1.0 mmol,0.239 g, 2.0 equiv) and DMF (2.0 mL). The mixture was degassed by the freeze-pump-thaw method and the reaction vessel was filled with argon. A 1 Watt blue light emitting diode(LED) strip was placed around the reaction vessel at a distance of approximately 2-4 cm. The reaction was stopped by removing the LED lamps and the mixture was poured into a separatory funnel containing ethyl acetate (10 mL) and water (10 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combinedorganic phases were washed with brine (10 mL), dried (anhydrous Na2SO4), filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC on a C18 column, using water and acetonitrile as eluent. Appropriate fractions were collected, frozen and lyophilized to afford derivatives of substrates as pure compounds.
Reference: [1] Synlett, 2017, vol. 28, # 8, p. 907 - 912
  • 33
  • [ 6146-52-7 ]
  • [ 166104-20-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 4, p. 1106 - 1110
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6273 - 6277
[3] Patent: WO2016/73652, 2016, A1,
[4] Patent: WO2016/176460, 2016, A1,
[5] Patent: CN104311541, 2017, B,
  • 34
  • [ 24424-99-5 ]
  • [ 6146-52-7 ]
  • [ 166104-19-4 ]
YieldReaction ConditionsOperation in experiment
100% at 0℃; for 0.0833333 h; Nitro-lH-indole (325 mg, 2.0 mmol)In dichloromethane (6 mL) was added di-tert-butyl dicarbonateEster (524 mg, 2.4 mmol),Stirred at 0 ° C for 5 minutes,A further catalytic amount of 4-dimethylaminopyridine (3 mg, 0.025 mmol) was added,Stirring is then continued for 30 minutes at room temperature.Quenched by adding water (2 mL)Extract with dichloromethane (15 mL x 3).The combined organic phase was washed with water (20 mL)Saturated brine (15 mL × 2)Dried over anhydrous sodium sulfate,The solvent was distilled off under reduced pressure,Obtained as a gray solid (526 mg, 100percent),Directly used for the next reaction.
99% With dmap In tetrahydrofuran at 0 - 20℃; for 3 h; Di-tert-butyl dicarbonate (8.07 g, 37.0 mmol)was siowly added to a stirred solution of 5-nitroindole (6.00 g, 37.0 mmol) and 4-dimethyianiinopyridine (226 Ing, 185 mmol) in THF (60 niL) at 0 °C. The mixture was then stirred for 3h at 20 °C. The reaction solution was concentrated in vacuo and the residue was dissolved in DCM (150 rnL). The organic layer was washed with water, brine, dried (MgSO4), filtered, and the solvent evaporated in vaeuo to yield the title compound (9.60 g, 99percent).
98% With triethylamine In dichloromethane at 0 - 20℃; Triethylamine (3.1 mL, 22.2 mmol) and 4-dimethylaminopyridine (226 mg, 1.85 mmol) were added to a solution of 5-nitro-1H-indole (3 g, 18.5 mmol) in DCM (30 mL) at 0° C., di-tert-butyl dicarbonate (4.3 g, 19.7 mmol) was then added.
The resulting mixture was warmed to room temperature and it was stirred overnight, it was then quenched by addition of water and extracted with DCM.
The organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure; the crude residue was filtered through a silica pad and the filtrate was evaporated under reduced pressure to give 4.77 g (98percent yield) of 5-nitro-indole-1-carboxylic acid tert-butyl ester.
89% With dmap In dichloromethane at 20℃; for 1 h; 4-DMAP (414.4 mg, 3.4 mmol) and di-tert-butyl dicarbonate (740.3 mg, 3.4 mmol) were added to 5-nitro- l //-indole (500.0 mg, 3.1 mmol) in DCM (5 mL), stirred for 1 h at ambient temperature, 2 M HCL was added followed by extraction with DCM, organic phase was collected and the solvent was removed un- der reduced pressure. Yield 724.0 mg (89percent). HPLC 100percent. LC-MS 263 (M+H)+.
78% With dmap In tetrahydrofuran; ethyl acetate Part F.
5-Nitro-1H-indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate (3.6 g, 17 mmol), and DMAP (190 mg, 1.5 mmol) were dissolved in 150 mL of THF.
The solution was stirred for 12 h at rt under N2 and was then concentrated.
The residue was taken up in EtOAc and the mixture was filtered.
The filtered solid was washed with 100 mL of hexanes and dried to give tert-butyl-5-nitro-1H-indole-1-carboxylate as an off-white solid (3.1 g, 78percent). LRMS (AP+): 304.2 (M+H+ACN)+. 1H NMR (CDCl3) δ8.51 (d, 1H), 8.23-8.29 (m, 2H), 7.75 (d, 1H), 6.73 (d, 1H), 1.71 (s, 9H).
78% With dmap In tetrahydrofuran at 20℃; for 12 h; Inert atmosphere Part F.
5-Nitro-1H-indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate (3.6 g, 17 mmol), and DMAP (190 mg, 1.5 mmol) were dissolved in 150 mL of THF.
The solution was stirred for 12 h at rt under N2 and was then concentrated.
The residue was taken up in EtOAc and the mixture was filtered.
The filtered solid was washed with 100 mL of hexanes and dried to give tert-butyl-5-nitro-1H-indole-1-carboxylate as an off-white solid (3.1 g, 78percent). LRMS (AP+): 304.2 (M+H+ACN)+. 1H NMR (CDCl3) δ 8.51 (d, 1H), 8.23-8.29 (m, 2H), 7.75 (d, 1H), 6.73 (d, 1H), 1.71 (s, 9H).
1 g With dmap; triethylamine In dichloromethane at 20℃; for 16 h; 1(1.0 g, 6.17 mmol), DCM (30 mL). DMAP (cat.), TEA (3 eq), (Boc)20 (1.2 eq) reacted at RT. After 16 h anon-polar product was observed by TLC. The reaction was quenched with ice cold water and extracted with DCM (2X10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by silica gel column chromatography [using 100-200 mesh, eluting with 10percent EtOAc-hexanej to afford 1 g of 2.

Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6273 - 6277
[2] Patent: CN104311541, 2017, B, . Location in patent: Paragraph 0162; 0163
[3] Synthesis, 2009, # 21, p. 3617 - 3632
[4] Patent: WO2016/176460, 2016, A1, . Location in patent: Page/Page column 96
[5] Patent: US2009/247568, 2009, A1, . Location in patent: Page/Page column 35-36
[6] Patent: WO2007/147874, 2007, A1, . Location in patent: Page/Page column 158-159
[7] Synlett, 2008, # 2, p. 294 - 296
[8] Patent: US2003/191115, 2003, A1,
[9] Patent: US2017/50964, 2017, A1, . Location in patent: Paragraph 0733
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6481 - 6488
[11] Journal of Medicinal Chemistry, 2011, vol. 54, # 4, p. 1106 - 1110
[12] Patent: WO2016/73652, 2016, A1, . Location in patent: Page/Page column 121
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  • [ 686747-51-3 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 2006, vol. 71, # 6, p. 899 - 911
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9875 - 9890
[3] Organic Letters, 2016, vol. 18, # 24, p. 6504 - 6507
[4] Patent: WO2007/135380, 2007, A2,
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Reference: [1] Patent: US2017/50964, 2017, A1,
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  • [ 6146-52-7 ]
  • [ 165250-69-1 ]
YieldReaction ConditionsOperation in experiment
4.1 mmol, 80% With methylmagnesium bromide; chloranil In tetrahydrofuran 4-Methyl-5-nitroindole
To a solution of 5-nitroindole (from Aldrich, 0.82 g, 5.1 mmol) in 20 mL of dry THF was added 5.0 mL (15 mmol) of methylmagnesium bromide for 0.5 h period and the resulting reaction mixture was stirred for 1 h at 25° C.
Reaction was the quenched by adding a THF solution of tetrachloro-1,4-benzoquinone (1.2 g, 4.9 mmol).
Reaction mixture was concentrated in vacuo, yielding a dark solid which was subjected to column chromatography (30percent EtOAc/n-Hexane) to yield 0.72 g (4.1 mmol, 80percent) of the desired product.
Reference: [1] Patent: US5677321, 1997, A,
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  • [ 6146-52-7 ]
  • [ 686747-19-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9875 - 9890
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  • [ 677702-36-2 ]
Reference: [1] RSC Advances, 2018, vol. 8, # 24, p. 13121 - 13128
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  • [ 6146-52-7 ]
  • [ 914349-07-8 ]
Reference: [1] Patent: CN107915726, 2018, A,
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