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Chemical Structure| 50820-65-0 Chemical Structure| 50820-65-0
Chemical Structure| 50820-65-0

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Product Details of Methyl 1H-indole-6-carboxylate

CAS No. :50820-65-0
Formula : C10H9NO2
M.W : 175.18
SMILES Code : O=C(C1=CC2=C(C=C1)C=CN2)OC
MDL No. :MFCD00211063
InChI Key :AYYOZKHMSABVRP-UHFFFAOYSA-N
Pubchem ID :639844

Safety of Methyl 1H-indole-6-carboxylate

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of Methyl 1H-indole-6-carboxylate

* 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.

  • Downstream synthetic route of [ 50820-65-0 ]

[ 50820-65-0 ] Synthesis Path-Downstream   1~32

  • 1
  • [ 50820-65-0 ]
  • [ 1670-82-2 ]
YieldReaction ConditionsOperation in experiment
95% With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; (c) A solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60 C. for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50% (v/v) hydrochloric acid. The precipitate which formed was collected by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95%) as a tan powder; mp 253-254: NMR (80 MHz; CDCl3) 6.51(m, 1H, H3 -indole), 8.04(m, 1H, H7 -indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH).
95% With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; (c) A solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60C for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50% (v/v) hydrochloric acid. The precipitate which formed was collect by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95%) as a tan powder; mp 253-254; NMR (80 MHz; CDCl3): 6.51(m, 1H, H3-indole), 8.04(m, 1H, H7-indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH).
88% Step 1: Lithium hydroxide (0.72 g, 17.2 mmol, 3 equiv.) in water (10 mL) was added to <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (1 g, 5.7 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and the mixture stirred at 80 C. for 16 hours. The solution was concentrated under vacuum then diluted with dichloromethane (10 mL) and the organic layer extracted with water (3×10 mL). The aqueous phase was acidified to pH<1 with concentrated HCl forming a precipitate. The precipitate was filtered and washed with 1 M aqueous HCl (3×10 mL) to afford 1H-indole-6-carboxylic acid as a white solid, 0.807 g (88% yield). LC (at)215 nm; Rt 1.02: 100%, m/z (ES+): 162 (M+H+.); δH (400 MHz; MeOD) 8.15 (1H, d), 7.72 (1H, m), 7.67 (1H, m), 7.45 (1H, m), 6.53 (1H, m).
85% To a solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (3.0 g) in MeOH (34 mL), a 3M aqueous solution of LiOH (17 mL, 3.0 equiv.) was added. The reaction mixture was heated at reflux for 1 Hr, then cooled at 0C, diluted with water (50 mL) and acidified with HCl 12M (5 mL). The mixture was extracted with AcOEt (3*30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and concentrated to give the product as a yellow solid (2.3 g, 85%). M/Z (M+H)+ = 162.
57% Step 4. 1H-Indole-6-carboxylic acid A solution of <strong>[50820-65-0]methyl 1H-indole-6-carboxylate</strong> (1.3 g, 7.43 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was placed into a 250-mL round-bottom flask. Then CH3OH (20 mL), H2O (10 mL), LiOH.H2O (1.9 g, 45.24 mmol, 6.09 equiv) were added. The resulting solution was stirred overnight at 60 C. The resulting mixture was concentrated in vacuo, and diluted with water. The resulting solution was extracted with 2*100 mL of ether and the aqueous layers were combined. The pH value of the solution was adjusted to pH 3 with hydrochloric acid, and the solids were collected by filtration. This resulted in 0.68 g (57%) of 1H-indole-6-carboxylic acid as a light yellow solid.

  • 2
  • [ 104447-80-5 ]
  • [ 50820-65-0 ]
YieldReaction ConditionsOperation in experiment
85% In tetrahydrofuran; palladium; ethyl acetate; b. Methyl indole-6-carboxylate A solution of methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (5.58 g) in tetrahydrofuran (100 ml) was hydrogenated at 3.45 bar in the presence of 10% (w/w) palladium on carbon (1.1 g) for 35 min. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the solution obtained was washed successively with 10% (v/v) hydrochloric acid, water, and brine; then dried (MgSO4) and evaporated to give methyl indole-6-carboxylate (3.32 g, 85%) as a white solid; NMR (80 MHz, CDCl3): 3.92(s, 3H, OCH3), 6.57(m, 1H, H3 -indole), 7.32(t, 1H, H2 -indole), 7.10(d, 1H, H4 -indole), 7.87(dd, 1H, H5 -indole), 8.16(broad s, 1H, H7 -indole).
85% In tetrahydrofuran; palladium; ethyl acetate; (b) A solution of methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (5.58 g) in tetrahydrofuran (100 ml) was hydrogenated at 3.45 bar in the presence of 10% (w/w) palladium on carbon (1.1 g) for 35 minutes. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the solution obtained was washed successively with 10% (v/v) hydrochloric acid, water, and brine, then dried (MgSO4) and evaporated to give methyl indole-6-carboxylate (3.32 g, 85%) as a white solid; NMR (80 MHz, CDCl3) 3.92(s, 3H, OCH3), 6.57(m, 1H, H3 -indole), 7.32(t, 1H, H2 -indole), 7.10(d, 1H, H4 -indole), 7.87(dd, 1H, H5 -indole), 8.16(broad s, 1H, H7 -indole).
85% In tetrahydrofuran; palladium; ethyl acetate; (b) A solution of methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (5.58 g) in tetrahydro-furan (100 ml) was hydrogenated at 3.45 bar in the presence of 10% (w/w) palladium on carbon (1.1 g) for 35 minutes. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the solution obtained was washed successively with 10% (v/v) hydrochloric acid, water, and brine, then dried (MgSO4) and evaporated to give methyl indole-6-carboxylate (3.32 g, 85%) as a white solid; NMR (80 MHz, CDCl3): 3.92(s, 3H, OCH3), 6.57(m, 1H, H3-indole), 7.32(t, 1H, H2-indole), 7.10(d, 1H, H4-indole), 7.87(dd, 1H, H5-indole), 8.16(broad s, 1H, H7-indole).
84% With hydrogen;palladium on activated charcoal; In tetrahydrofuran; at 20℃; Step 3. Methyl 1H-indole-6-carboxylate A solution of (E)-methyl 4-(2-(dimethylamino)vinyl)-3-nitrobenzoate (2.2 g, 8.80 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) was placed into a 100-mL round-bottom flask. Then 2.4 g of palladium on carbon was added. An atmosphere of hydrogen gas was placed over the contents of the flask, and the reaction was stirred overnight at room temperature. Then the solids were filtered off, and the resulting mixture was concentrated in vacuo. This resulted in 1.3 g (84%) of methyl 1H-indole-6-carboxylate as brown oil.
With sodium dithionite; In tetrahydrofuran; ethanol; water; Production Example 5 6-methoxycarbonylindole To a mixed solvent of tetrahydrofuran (30 ml), ethanol (30 ml) and water (100 ml), added are methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (10.0 g) and sodium hydrosulfite (104.5 g), and stirred at 70 C. for 1 hours. After this is cooled to room temperature, a saturated saline solution is added thereto. Then, this is extracted with chloroform. The organic layer is dried, and the solvent is evaporated away. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/1) to obtain 6-methoxycarbonylindole (2.79 g). 1H-NMR (CDCl3, δ): 3.93 (3H, s), 6.60 (1H, s), 7.37 (1H, m), 7.66 (1H, d, J=8.3 Hz), 7.81 (1H, dd, J=1.3 and 8.3 Hz), 8.17 (1H, s), 8.52 (1H, brs).
palladium-carbon; In tetrahydrofuran; EXAMPLE 1 Methyl 6-indolecarboxylate STR8 16.7 g (0.060 mol) of methyl 4-(2-dimethylaminoethenyl)-3-nitrobenzoate [prepared according to the general working procedure of L. F. Tietze and Th. Eicher, "Reaktionen und Synthesen" (Reactions and Syntheses), p. 172, Thieme, Stuttgart 1981] were hydrogenated in 300 ml of tetrahydrofuran containing 1.1 g of palladium carbon (10%). The solution was filtered for 2 hours through kieselguhr and the catalyst was washed with 50 ml of tetrahydrofuran. The solvent was removed in vacuo. In order to remove a small amount of impurity (methyl 3-amino-4-methylbenzoate), the product was washed successively with 10% strength hydrochloric acid, water and concentrated sodium chloride solution, dried over magnesium sulphate and concentrated on a rotary evaporator. Yield: 9.9 g (94% of theory) of yellow crystals Rf (CH2 Cl2)=0.38 Rf (CH2 Cl2, 5% MeOH)=0.53

  • 3
  • [ 50820-65-0 ]
  • [ 341988-36-1 ]
YieldReaction ConditionsOperation in experiment
77% Step 1: A solution of indole-6-carboxylic acid methyl ester (534 mg, 3.05 mmol) in acetic acid (7.5 ml) was cooled to 0° C. Sodium cyanoborohydride (580 mg, 9.2 mmol, 3 equiv.) was added and the mixture stirred at 15° C. for 40 min. A further aliquot of sodium cyanoborohydride (193 mg, 3.05 mmol, 1 equiv.) was added, and the reaction mixture was stirred for 30 min. at room temperature. The solvent was then evaporated, and the residue dissolved in dichloromethane and washed with 1N NaOH. The organic phase was dried with Na2SO4 and evaporated, yielding 2,3-dihydro-1H-indole-6-carboxylic acid methyl ester as a light yellow solid, 494 mg (77percent). This was used as such in the following reaction.
77% A solution of indole-6-carboxylic acid methyl ester (534 mg, 3.05 mmol) in acetic acid (7.5 ml) was cooled to 0° C. Sodium cyanoborohydride (580 mg, 9.2 mmol, 3 equiv.) was added and the mixture stirred at 15° C. for 40 min. A further aliquot of sodium cyanoborohydride (193 mg, 3.05 mmol, 1 equiv.) was added, and the reaction mixture was stirred for 30 min. at room temperature. The solvent was then evaporated, and the residue dissolved in dichloromethane and washed with 1N NaOH. The organic phase was dried with Na2SO4 and evaporated, yielding 2,3-dihydro-1H-indole-6-carboxylic acid methyl ester as a light yellow solid, 494 mg (77percent). This was used as such in the following reaction.
76% With sodium cyanoborohydride; acetic acid; at 20℃; The title compound was prepared according to General Procedure G from methyl indoe~6- carboxylate (200 mg, 1.14 mmo). The crude product was purified b Combifiash silica gel chromatography (0-30percent of EtOAc in hexane), which provided 153 mg (76percent) of the title compound as a colorless solid; NMR (400 MHz, CD ) delta - 7.51 (dd, J = 1,5, 7.6 Hz, 1 H), 7.39 (d, J ~ 15 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 3.89 (s, 3 H), 3.67 ( , J = 8,5 Hz, 2 H), 3.12 (t, J *= 8,5 Hz, 2 H). General Procedure 6; Reduction of indole in indolin-e. To the solution of indole (1 eq.) in AcOH (C; 0,5 rnmo) at room temperature was added N38H3CN (3 eq.). The reaction was stirred at the same temperature for 2~4h, The completion of the reaction was monitored by HPLC. Upon completion, H2O was added and the reaction mixture was concentrated to dryness. H2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCCh, brine and dried over a^SQ^ Filtratio and removal of the solvent provided the desired product, which was used without further purification or purified by Combiflash silica gel chromatography to give the corresponding products.
75% With sodium cyanoborohydride; acetic acid; In dichloromethane; at 0 - 25℃; NaCNBH3 (11.49 g; 0.04 equiv.) was added at 0° C., over a period of 10 minutes, to a solution of methyl 1H-indole-6-carboxylate (8 g; 1 equiv.) in acetic acid (80 ml). The reaction mixture was stirred at 0° C. for 20 minutes and then warmed to room temperature and stirred for 1 hour at room temperature. When the conversion was complete, the acetic acid was distilled off under reduced pressure and the resulting residue was dissolved in dichloromethane. The resulting phases were separated. The organic phase was washed with 1N sodium hydroxide solution and dried over sodium sulfate. After removal of the solvent under reduced pressure, purification was carried out by column chromatography (silica gel, 10-15percent ethyl acetate/hexane). Methyl indoline-6-carboxylate (6 g; 75percent) was obtained in the form of a solid.
73% With sodium cyanoborohydride; acetic acid; at 15℃; for 5h; A solution of methyl lH-indole-6-carboxylate ( 4.80 g, 27.4 mmol ) in acetic acid ( 40 mL ) was cooled to 15 0 C and then treated with sodium cyanoborohydride ( 6.90 g, 0.11 mmol ) added in small portions over 30 min. After 5 h at 15 ° C, the reaction mixture was diluted with a mixture of ice and water ( 200 mL) and carefully adjusted to pH 9 -10 with solid potassium carbonate. The aqueous phase was extracted three times with dichloromethane and the combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residual oil was chromatographed on silica gel ( elution toluene - ethyl acetate 8 : 2 ) to give 3.54 g ( 73 percent yield ) of the title material as yellowish solid. HPLC (Method A): 0.9 min ( tailing ). HRMS (ESI) calcd for Ci0H12NO2 [M+H]+ m/z 178.0863, found 178.0882. 1H NMR (CDC13, 400 MHz) delta ppm: 7.40 (dd, J = 7.6, 1.5 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.12 (br. d, J = 7.6 Hz, 1H), 3.85 (s, 3H), 3.59 (t, J = 8.5 Hz, 2H), 3.05 (t, J = 8.5 Hz, 2H).
49% A stirred solution of 2A (1 g, 5.7 mmol) in DCM (20 ml_) and TFA (10 mL) at -200C was treated with Et3SiH (10 mL). The reaction was warmed to RT slowly and stirred thereafter for 17 h. The reaction was quenched with 2 N NaOH until pH 8. The mixture was extracted with DCM (100 mL x 3). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography (20percent EtOAc/hexanes) provided 2B (0.5g, 49percent).
24% With sodium cyanoborohydride; acetic acid; at 30℃; for 16h; To a solution of methyl IH-indole-6-carboxylate (5.0 g, 28.54 mmol) in AcOH (30 mL) wasadded NaBH3CN (5.4 g, 85.62 mmol). The mixture was stirred at 30 °C for 16 h. The reactionwas quenched with sat. aq. NaHCO3 (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc = 50 : I to 3 : I) to give the title compound (1.2 g, 24percent) as a whitesolid. ?H NMR (400 MHz, DMSO-d6) oe 7.16 (d, J7.6 Hz, IH), 7.14 (d, J=7.6 Hz, IH), 5.75 (s, IH), 3.78 (s, 3H), 3.52 (t,J 8.4 Hz, 2H), 2.95 (t,J 8.4 Hz, 2H).
With sodium cyanoborohydride; acetic acid; at 0 - 15℃; for 2h; Dissolve methyl indole-6-carboxylate (5.00 g, 28.5 mmol) in acetic acid (50 mL)In a 100 mL single-mouth bottle, sodium cyanoborohydride (8.85 g, 142 mmol) was slowly added at 0 °C.After completion, the reaction was carried out at 15 ° C for 2 hours. After the reaction is complete,The reaction solution was dried to dryness and then purified and evaporated with methylene chloride (200 mL).Extracted with dichloromethane (150 mL × 3),The combined organic phases were dried and concentrated to give the title compound.

  • 5
  • [ 50820-65-0 ]
  • [ 74-88-4 ]
  • [ 1204-32-6 ]
YieldReaction ConditionsOperation in experiment
100% To a stirred solution of methyl 1 H-indole-6-carboxylate (0.76g, 4.34mmol) in DMF (10ml) at room temperature was added sodium hydride (0.35g, 8.75mmol). The resultant suspension was stirred for 30min at room temperature followed by the addition of methyl iodide (0.54ml, 8.67mmol). The reaction mixture was stirred for 2Oh at room temperature and was then quenched by the addition of water (20ml) and ethyl acetate (20ml). The aqueous layer was extracted with ethyl acetate (3 x 30ml) and the combined extracts were dried with a phase separating column. The solvent was then removed in vacuo to give the desired product as an off-white solid (0.85g, 100%). LC-MS (Acidic) (MH+=I 90). The product was used without further purification
100% Method D; 1 -methyl-1 /-/-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (Intermediate compound); A mixture of methyl-indole-6-caroxylate (3.0 g, 16.6 mmol), sodium hydride (1.0 g, 24.9 mmol), DMF (20 ml) was stirred for 1 h at room-temperature followed by addition of iodomethane (4.7 g, 33.2 mmol) and stirring at room- temperature for 15 h. The mixture was extracted with chloroform and evaporated. The product was isolated by evaporation. Yield 3.2 g (100%).
In N-methyl-acetamide; i 1-methyl<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> To a stirred solution of methyl 6-indolecarboxylate (5 g) in dry dimethylformamide (30 ml) cooled to 5 C., sodium hydride (60% dispersion in oil, 1.49 g) was added portionwise. The reaction mixture was stirred at 5 C. for 0.5 hour, then a solution of methyliodide (12.18 g) in dry dimethylformamide (10 ml) was added dropwise. After 2 hours, the reaction mixture was diluted with water and the product obtained, after cooling and filtration.
1.16 g With potassium hydroxide; In dimethyl sulfoxide; at 20℃; for 1h; Method 3 Synthesis of methyl 1-methylindole-6-carboxylate (Intermediate 4) To a solution of R-3 (1 g, 5.7 mmol) in DMSO (10 mL) is added KOH (800 mg, 14.3 mmol) and iodomethane (0.534 mL, 8.6 mmol). After stirring at room temperature for 1 h the reaction mixture is diluted with water (50 mL) and the resultant suspension filtered and washed with more water. The solid is dried in vacuo to give the title intermediate I-4 (1.16 g) m/z 190.0 [M+H].
With sodium hydroxide; In N-methyl-acetamide; REFERENCE EXAMPLE 5 Preparation of methyl 1-methyl-6-indolecarboxylate The reaction was carried out in a manner similar to Reference Example 4 except for using 3.00 (17.1 mmol) of methyl 6-indolecarboxylate, 0.68 g (17.1 mmol) of 60% sodium hydroxide, 4.86 g (34.4 mmol) of methyl iodide and 60 ml of dimethylformamide. Thus 2.75 g (86.9%) of methyl 1-methyl-6-indolecarboxylate was obtained. 1H NMR (CDCl3) δ: 3.86 (3H, s), 3.95 (3H, s), 6.51-6.53 (1H, m), 7.21 (1H, d, J=3.3 Hz), 7.63 (1H, d, J=8.6 Hz), 7.78-7.82 (1H, m), 8.10 (1H, S).

  • 6
  • [ 50820-65-0 ]
  • [ 100-39-0 ]
  • [ 192997-33-4 ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of commercially available <strong>[50820-65-0]methyl 1H-indole-6-carboxylate</strong> (500 mg,2.85 mmol) in dry DMF (10 mL) was added NaH (68.49 g, 2.85 mmol, 60% suspension inmineral oil) and the whole stirred at RT for 1 h. Benzyl bromide (0.372 g, 3.142 mmol) wasthen added and the whole stirred at RT for 3 h. Progress of the reaction was monitored byTLC and LCMS and after completion the reaction; the reaction mixture was diluted withMTBE and filtered through a short celite bed. The filtrate was extracted with MTBE, organiclayer was washed with with brine and dried over anhydrous Na2SO4 and evaporated to givethe title compound (500 mg) as a crude solid which was used in next step without any furtherpurification. LCMS
  • 7
  • [ 50820-65-0 ]
  • [ 1075-26-9 ]
YieldReaction ConditionsOperation in experiment
95% With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 3h;Under nitrogen; Preparation XLVII 6-((triisopropylsilyloxy)methyl)indole indole-6-carboxylic Acid Methyl Ester [0339] To a solution of indole-6-carboxylic acid (39.5 g, 245 mmol) in methanol (200 mL) and dichloromethane (750 mL) was added 2 M (trimethylsilyl)diazomethane in hexanes (160 mL, 320 mmol) dropwise over 1 hour. The reaction was stirred at room temperature overnight. The following day the reaction was concentrated to a thick brown crude oil that was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (2×200 mL), saturated aqueous sodium chloride (2×200 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate concentrated under reduced pressure to form a suspension. The suspension was filtered to provide 43 g of the desired compound as an off-white solid. [0340] 6-(hydroxymethyl)indole [0341] To a solution of <strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (20.0 g, 114 mmol) in anhydrous tetrahydrofuran (1.6 L) stirring under nitrogen at room temperature was added carefully lithium aluminum hydride (8.7 g, 230 mmol) while purging with nitrogen. Following this addition, the reaction mixture was stirred at room temperature for 3 hours and was then cooled to 0 C. This mixture was treated sequentially with water (9 mL), 15% sodium hydroxide (9 mL), and additional water (25 mL). The resulting suspension was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 30%-60% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 16.0 g (95%) of the desired compound as an off-white solid. [0342] IS-MS, m/e 146.0 (m-1). [0343] Silylation [0344] To a solution of 6-(hydroxymethyl)indole (16.0 g, 110 mmol) in dichloromethane (800 mL) stirring at 0 C. under nitrogen was added triethylamine (22.5 mL, 160 mmol). Next a prepared solution of triisopropylsilyl trifluoromethanesulfonate (30.5 mL, 115 mmol) in dichloromethane (200 mL) was added slowly using an addition funnel. The reaction was stirred at 0 C. for 3 hours. The reaction was then diluted with dichlormethane (200 mL) and washed with water (2×200 mL), saturated aqueous sodium chloride (2×200 mL) and dried over sodium sulfate. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was sujected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide the title compound. [0345] IS-MS, m/e 302 (m-1).
With hydrogenchloride; In tetrahydrofuran; sodium-dried tetrahydrofuran; water; EXAMPLE 9 6-Hydroxymethyl indole Lithium aluminium hydride (3.48 g, 91.70 mmol) was suspended in sodium-dried tetrahydrofuran (150 ml). The suspension was stirred under a nitrogen atmosphere. Methyl-(indol-6-yl)methanoate (8.0 g, 45.7 mmol) was dissolved in dry tetrahydrofuran (50 ml) and added dropwise to the lithium aluminium hydride suspension. The mixture was stirred at ambient temperature for three hours. Water (10 ml) was added dropwise, followed by 2N hydrogen chloride (30 ml). The mixture was extracted with diethyl ether (3*150 ml) to yield a light purple oil.
2.05 g To a suspension of lithium aluminium hydride (0.866 g; 22.82 mmol) in dry THF (30 mL) cooled at 0 C was added a solution of methyl 1 /-/-indole-6-carboxylate (2.000 g; 1 1 .42 mmol) in THF (30 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by careful addition of a 1 N Rochelle salt solution. The reaction mixture was stirred at room temperature for 2 h and was then extracted with dichloromethane. The phases were separated. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure to afford 2.050 g of (1 /-/-indolyl-6-yl)methanol as a yellow oil which was used in the next step without further purification. ESI/APCI(-): 146 (M- H).
  • 8
  • [ 50820-65-0 ]
  • [ 589-87-7 ]
  • 2-(4-bromophenyl)-1H-indole-6-carboxylic acid methyl ester [ No CAS ]
  • 9
  • [ 50820-65-0 ]
  • [ 108-94-1 ]
  • [ 494799-16-5 ]
YieldReaction ConditionsOperation in experiment
100% Example 1; Preparation of (2E)-3-{4-[({1-[({3-CycIohexyl -1-[2- (dimethylamino) - 2-oxoethyl -2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopenthyl}carbonyl) amino]phenyl }acrylic acid; Step 1; 3-Cyclohex-1-en-1-yl-1H-indole-6-carboxylic acid; To a solution of methyl-indole-6-carboχylate in MeOH (1,7 M) was added cyclohexanone (3.0eq.) followed by 30% NaOMe in MeOH (6,0 eq.) in 100 ml portions over 20 min. The resulting mixture was stirred at RT for 45 min and relaxed for 8 h. Water was added, and the mixture stirred at RT until all solids had dissolved. The organic solvent was removed under vacuum and the pH of the aqueous phase adjusted to 1, by slow addition of concentrated HCl at 0 C. The precipitate was isolated by filtration, and then washed with water, until the pH of the water reached 6- 7, Drying under high vacuum gave the title compound as a beige solid (100%),
97.5% 3-Cyclohexenyl-1H-indole-6-carboxylic acid.; Cyclohexanone (96 mL, 0.926 mol) was added to a stirred solution of methyl indole-6-carboxylic acid (50.0 g, 0.335 mol) in methanol (920 mL) at 22 C. Methanolic sodium methoxide (416 mL of 25% w/w, 1.82 mol) was added in portions over 10 minutes. The mixture was stirred at reflux for 18 hours, cooled to room temperature, concentrated, diluted with cold water, and acidified with 36% HCl solution. The resulting precipitate was collected by filtration, washed with cold water, and dried over phosphorous pentoxide (0.1 mm) to provide the title compound as a tan colored solid (80.9 g, 97.5% yield).
58% With water; potassium hydroxide; In methanol; at 75℃; for 18h; To a stirred solution of compound 26 (2 g, 11.4 mmol) and cyclohexanone (3.36 g,34.2 mmol) in MeOH (15 mL), aqueous KOH (1.92 g, 34.2 mmol, dissolved in 13 mL water) was added. The resulting reaction mixture was stirred at 75 C for 18 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water, acidified with acetic acid pH-6; the obtained solidwas filtered; washed with water and dried in vacuo to afford the crude. The crude compound was triturated with IPA to afford compound 34 (1.6 g, 58%) as light brown solid. ‘H-NMR (400 MHz, DMSO-d6): ? 11.33 (s, 1H), 7.97 (s, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.61 (d, J= 8.4 Hz, 1H), 7.47 (s, 1H), 6.19 (s, 1H), 2.42 -2.39 (m, 2H), 2.22 - 2.20 (m, 2H), 1.76 - 1.72 (m, 4H). LCMS observed (m/z): 242 (M+1).
  • 10
  • [ 872-50-4 ]
  • [ 50820-65-0 ]
  • [ 1005458-15-0 ]
YieldReaction ConditionsOperation in experiment
57% Step 1 3-[1-Methyl-pyrrolidin-(2Z)-ylidene]-3H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> A mixture of 1.6 mL (16 mmol) 1-methyl-2-pyrrolidone and 10 mL phosphoryl chloride (POCl3) in 10 mL 1,2-dichloroethane was stirred for 15 min and 1.75 g (10 mmol) <strong>[50820-65-0]methyl indole-6-carboxylate</strong> and 1.6 mL (16 mmol) 1-methyl-2-pyrrolidone in 10 mL 1,2-dichloroethane was added. The mixture was heated to reflux for 2 h. Water and Na2CO3 aq. was added to adjust to pH=9. Subsequently the mixture was extracted with DCM and the combined organic layers were washed with water, dried with Na2SO4 and evaporated to dryness. Trituration with acetone provided 1.45 g (57%) of the title compound as light brown solid. MS (m/e): 257.2 (MH+).
  • 11
  • [ 4783-65-7 ]
  • [ 50820-65-0 ]
  • [ 1005458-24-1 ]
YieldReaction ConditionsOperation in experiment
9% Step 1 3-(1-Benzyl-piperidin-2-yl)-1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> A mixture of 7.08 g (40 mmol) <strong>[50820-65-0]methyl indole-6-carboxylate</strong>, 12.5 g (66 mmol) 1-benzyl-2-piperidone and 8.16 g (53 mmol) POCl3 in 60 mL 1,2-dichloroethane was heated to reflux for 2 h. The mixture was poured onto ice/water, adjusted to pH=9 with Na2CO3 aq (10%) and extracted with DCM. The combined organic phases were washed with NaCl aq. dried with Na2SO4 and evaporated to dryness. The residue was taken up with isolute and purified by column chromatography on silica eluding with a gradient formed from DCM/methanol/NH3 aq. The product fractions were evaporated and used without further purification in the subsequent reaction by addition of 200 mL methanol and 3.37 g (89 mmol) sodium borohydride (NaBH4) and stirring for 40 h at room temperature. After evaporation DCM, water and Na2CO3 aq. was added and the organic layer was washed with NaCl aq., dried with Na2SO4. and evaporated to dryness. The residue was taken up with isolute/DCM and after evaporation purified by column chromatography on silica eluding with a gradient formed from DCM/methanol/NH3 aq. The product fractions were evaporated to yield 1.25 g (9%) of the title compound as light yellow solid. MS (m/e): 349.2 (MH+).
  • 12
  • [ 50820-65-0 ]
  • [ 79-04-9 ]
  • [ 1005458-26-3 ]
YieldReaction ConditionsOperation in experiment
20% With ethylmagnesium chloride; zinc(II) chloride; In tetrahydrofuran; diethyl ether; dichloromethane; at 20℃; for 19h; Step 1 3-(2-Chloro-acetyl)-1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> A mixture of 14 g (80 mmol) <strong>[50820-65-0]methyl indole-6-carboxylate</strong>, 40 mL (84 mmol) ethylmagnesium chloride (2M) in diethyl ether, 240 mL (240 mmol) zinc chloride (1M) in diethyl ether, 9.5 g (84 mmol) chloroacetyl chloride in 680 mL DCM was stirred at room temperature for 19 h. THF was added and diethyl ether and DCM were removed by evaporation. The mixture was treated with NH4Cl aq. and ethyl acetate. The aqueous phase was extracted with THF/ethyl acetate and the combined organic layers were washed with NaCl aq., dried with Na2SO4 and evaporated. The residue was washed with ethyl acetate and dried under vacuum at 50 C. to yield 4 g (20%) of the title compound as light yellow solid. MS (m/e): 250.1 (M-H).
  • 13
  • [ 50820-65-0 ]
  • [ 2550-36-9 ]
  • [ 182345-37-5 ]
YieldReaction ConditionsOperation in experiment
74% To a solution of commercially available l//-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (0.35 g, 2.0 mmol) and cyclohexylmethyl bromide (0.31 mL, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:24) to provide l-cyclohexylmethyl-l//-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> as a white solid (0.40 g, 74% yield). 1H NMR (400 MHz, DMSO) δ 8.10 (s, IH), 7.62 (m, 2H), 7.58 (d, IH, J = 3.1 Hz), 6.52 (d, IH, J= 3.1 Hz), 4.10 (d, 2H, J= IA Hz), 3.85 (s, 3H), 1.77 (m, IH), 1.65-1.57 (m 3H), 1.46 (m, 2H), 1.19 (m, 3H), 0.98 (m, 2H).
32% With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 8h; 1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (300mg, 1.71mmol) was dissolved in dimethyl formamide (7ml). Bromomethyl cyclohexane (0.5ml, 3.42mmol) and sodium hydride (150mg, 3.42mmol) were added dropwise thereto at 0, and then the mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (150mg, 32%). [611] NMR:1H-NMR(400HMz, CDCl3); δ 7.29-7.39 (m, 2H), 7.19 (d, 1H), 7.13 (m, 1H), 7.00-7.09 (m, 2H), 6.66 (m, 1H), 4.83 (s, 2H), 2.06 (s, 3H)
  • 14
  • [ 50820-65-0 ]
  • [ 3447-53-8 ]
  • [ 950763-28-7 ]
YieldReaction ConditionsOperation in experiment
21% To a solution of commercially available l//-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (0.35 g, 2.0 mmol) and 4-difluoromethoxy-benzyl bromide (0.52 g, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3.5 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1 :5) to provide l-(4-difluoromethoxy-phenylmethyl)-l//-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> as a colorless oil (0.14 g, 21% yield).
  • 15
  • [ 50820-65-0 ]
  • [ 2746-25-0 ]
  • [ 950763-29-8 ]
YieldReaction ConditionsOperation in experiment
54% To a solution of commercially available li/-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (0.35 g, 2.0 mmol) and 4-methoxybenzyl bromide (0.32 mL, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol).After stirring at room temperature for 3.5 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:5) to provide l-(4-methoxy-phenylmethyl)-l//'-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> as a white solid (0.32 g, 54% yield). 1H NMR (400 MHz, DMSO) δ 8.10 (s, IH), 7.73 (d, IH, J= 3.4 Hz), 7.64 (m, 2H), 7.14 (d, 2H, J= 9.0 Hz), 6.88 (d, 2H, J = 9.0 Hz), 6.58 (d, IH, J= 3.4 Hz), 5.45 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H).
  • 16
  • [ 50820-65-0 ]
  • [ 3958-57-4 ]
  • [ 950763-30-1 ]
YieldReaction ConditionsOperation in experiment
76% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; To a solution of l/f-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (1.0 g, 5.7 mmol) and 3-nitrobenzyl bromide (1.48 g, 6.8 mmol) in DMF (15 mL) was added K2CO3 ( 1.6 g, 11.4 mmol). After stirring at room temperature for 16 hr, the solution was diluted with ethyl acetate (100 ml) and washed with water (3 X 50 ml). The organic layer was <n="96"/>dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized with ethyl acetate/hexane to provide 1.34 g (76% yield) of l-(3-nitrobenzyl)-l//-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> as light orange crystals. 1H NMR (300 MHz, DMSO) δ 8.13 (m, 2H), 8.03 (s, IH), 7.81 (d, IH, J= 3.0 Hz), 7.67-7.54 (m, 4H, J= 9.0 Hz), 6.65 (d, IH, J= 3.0 Hz), 5.73 (s, 2H), 3.81 (s, 3H).
76% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; To a solution of lH-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (1.0 g, 5.7 mmol) and 3- nitrobenzyl bromide (1.48 g, 6.8 mmol) in DMF (15 mL) was added K2CO3 (1.6 g, 11.4 mmol). After stirring at room temperature for 16 hr, the solution was diluted with ethyl acetate (100 ml) and washed with water (3 X 50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized with ethyl acetate/hexane to provide 1.34 g (76% yield) of l-(3-nitrobenzyl)-lH-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> as light orange crystals. [00533] 1H NMR (300 MHz, DMSO) δ 8.13 (m, 2H), 8.03 (s, IH), 7.81 (d, IH, J= 3.0 Hz), 7.67- 7.54 (m, 4H, J= 9.0 Hz), 6.65 (d, IH, J= 3.0 Hz), 5.73 (s, 2H), 3.81 (s, 3H).
  • 17
  • [ 50820-65-0 ]
  • [ 75-36-5 ]
  • [ 106896-61-1 ]
YieldReaction ConditionsOperation in experiment
99% With aluminum (III) chloride; In dichloromethane; at 20℃; for 1h; To a solution of acetyl chloride (0.23 mL, 3.3 mmole) and aluminum chloride (0.88 g, 6.6 mmol) in methylene chloride (30 mL) was added l//-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (0.53 g, 3.0 mmol). After stirring 1 hr at room temperature water (300 mL) was added and then this was extracted with ethyl acetate (300 mL). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.65 g (99% yield) of 3-acetyl-l/f-indole-6- carboxylic acid methyl ester a light yellow solid. 1H NMR (300 MHz, DMSO) δ 12.27 (s, IH), 8.52 (s, IH), 8.24 (d, IH, J= 8.2 Hz), 8.08 (d, IH, J= 1.0 Hz), 7.78 (dd, IH, J= 8.2, 1.0 Hz), 3.86 (s, 3H), 2.47 (s, 3H).
625 mg With aluminum (III) chloride; In dichloromethane; at 20℃; for 1h; To a solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (1.01 g) in dichloromethane (30 mL) were added aluminum chloride (1.53 g) and acetyl chloride (0.5 mL) at room temperature, and then the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (625 mg) as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 8.34 (1H, s), 8.29 (1H, dd, J = 8.5, 0.7 Hz), 8.15 (1H, dd, J = 1.5, 0.7 Hz), 7.87 (1H, dd, J = 8.5, 1.5 Hz), 3.92 (3H, s), 2.54 (3H, s).
  • 18
  • [ 50820-65-0 ]
  • [ 3282-30-2 ]
  • methyl 1-(pivaloyl)-1H-indole-6-carboxylate [ No CAS ]
  • 20
  • [ 50820-65-0 ]
  • [ 494799-19-8 ]
YieldReaction ConditionsOperation in experiment
Step 1: methyl 2-bromo-l-(2-tert-butoxy-2-oxoethyl)~3-cvcloheχyl-lH-indole-6-carboxylate; NaH (1.4 eq, 60 % dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl- lH-indole-6-carboxylate (prepared as described in published International Patent application WO 2004/065367, from commercially available <strong>[50820-65-0]methyl indole-6-carboxylate</strong>) in DMF (0.2 M) and the solution stirred at RT for Ih. Then tert-butyl bromoacetate (1.1 eq) was added and the mixture stirred at RT for 40 min. The solvent was removed in vacuo and the residue taken up in EtOAc. The organic phase was washed with H2O (twice) and then brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound as a brownish solid (90 %); MS (ES+) m/z 450 (M+H)+, m/z 452 (M+H)+; Step 1: methyl 2-bromo-3-cyclohexyl-l -( 1.3-dioxolan-2-ylmethyl)-l H-indole-6-carboxylate; NaH (1.5 eq, 60 % dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl- lH-indole-6-carboxylate (prepared as described in published International Patent application WO 2004/065367, from commercially available <strong>[50820-65-0]methyl indole-6-carboxylate</strong>) in DMF (0.1 M) and once effervescence had subsided the solution was stirred at RT for a further 30 min. 2-bromomethyl-l,3- dioxolane (4 eq) and catalytic (0.025 eq) KI were then added and the mixture heated at 50 0C for 36 h. The reaction mixture was then allowed to cool to RT, quenched with aqueous HCl (1 N) and extracted EPO <DP n="26"/>with EtOAc. The organics were washed with aqueous HCl (1 N) (3x), water and brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo. Purification was by flash chromatography (10 % EtOAc/PE) to give a pale yellow solid that was triturated with Et2O/PE) to afford the title compound as a white solid (69 %); MS (ES+) m/z 422 (M+H)+, m/z 424 (M+H)+.; Step 1: methyl l-fl-ffftert-butoxycarbonyttaminolmethyli^-fluorophenvtt-S-cvclohexyl-lH-indole-- carboxylate; To a solution of methyl 2-bromo-3-cyclohexyl-lH-indole-6-carboxylate (prepared as described in published International patent application WO2004/087714, from commercially available methyl indole- 6-carboxylate) in dioxane (0.07 M) was added 0.2 eq of bis(triphenylphosphine)palladium(II) dichloride at RT under a nitrogen atmosphere. Then aqueous Na2CO3 (2 M solution, 2 eq.) and [2-(N-tert- butoxycarbonyl-amino-methyl)-4-fluorophenyl]-boronic acid (2 eq.) were added and the reaction flask immersed in a preheated oil bath at 100 0C for 2 h. The reaction mixture was allowed to cool and filtered. The filtrate was diluted with DCM and the organic phase washed with H2O, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude material was purified by flash chromatography ( 1 :9 EtOAc/PE) to afford the title compound as a solid (87 %); MS (ES+) m/z 481 (M+H)+.; Step 1: 3-[2-bromo-3-cyclohexyl-6-(methoxycarbonyl)-lH-indol-l-yl]propanoic acid; NaH (3.5 eq, 60 % dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl- lH-indole-6-carboxylate (prepared as described in WO 2004065367, from commercially available <strong>[50820-65-0]methyl indole-6-carboxylate</strong>) in DMF (0.2 M) and the solution allowed to stir at RT for 1 h. Then 3- bromopropanoic acid (1.1 eq) was added and the mixture stirred at RT for 2 h. DMF was concentrated in vacuo and the residue taken up in EtOAc. The organic phase was washed with 1 N HCl and then brine before being dried (Na2SO4), filtered and the solvent evaporated in vacuo. The title compound was used crude in the next step; MS (ES+) m/z 408 (M+H)+, m/z 410 (M+H)+.
  • 21
  • [ 67-56-1 ]
  • [ 1670-82-2 ]
  • [ 50820-65-0 ]
YieldReaction ConditionsOperation in experiment
91.9% With sulfuric acid; at 70℃; for 15h; To a solution of lT7-indole-6-carboxylic acid (2 g, 12.41 mmol, 1 eq) in MeOH (100 mL) was added H2SO4 (1.84 g, 18.76 mmol, 1 mL, 98%, 1.51 eq). The mixture was stirred at 70 C for 15 h. TLC (PE/EtOAc = 3/1, Rf= 0.47) showed the starting material was consumed completely. The reaction mixture was quenched with sat.aq NaHCCh (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers dried over Na2S04, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf= 0.43) to yield methyl 1 //-indole-6- carboxylate (2 g, 11.42 mmol, 91.9% yield, 100.0% purity) as a white solid. ^ MR (500 MHz, DMSO-i/e) S ppm 11.50 (s, 1H), 8.08 (s, 1H), 7.64-7.52 (m, 3H), 6.53 (t, J= 1.9 Hz, 1H), 3.87- 3.82 (m, 3H); ES-LCMS m/z 176.3 [M+H]+.
88% sulfuric acid; for 16h;Heating / reflux; Step 1; 1-2 Step 2 1-3 0 Step 3 NaH, Mel 5 t . fnn N CO, Me Stem 4 Step 4 F lla F 1-5 14 F F 0 Step 1 : Indole-6-carboxylic acid 1-1 (5. 0 g, 31.0 mmol) was dissolved in MeOH (100 mL), a catalytic amount of H2SO4 (1.0 mL) was added and the reaction mixture was stirred at reflux for 16 h. A small amount of solid K2CO3 was added, in order to neutralize the excess H2SO4, and stirring was continued at RT for 1 h. The reaction mixture was concentrated under vacuum to remove the MeOH, diluted with saturated aqueous NaHC03 (-50 mL) and extracted with EtOAc (-200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous MgS04 and concentrated to dryness. The resulting residue was purified by flash column chromatography, using 30% EtOAc in hexane as the eluent, to obtain the pure methyl ester 1-2 (4.78 g, 88% yield).
88% To a stirred solution of 1 H-indole-6-carboxylic acid (1.5 g, 9.31 mmol) in MeOH (200 mL) was added cone. H2SO4 (3 mL). The reaction was refluxed for 15 h and cooled to RT. The mixture was neutralized with sat. NaHCO3 and MeOH was removed under reduced pressure. The remaining mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography (20% EtOAc/hexanes) provided 2A (1 Ag, 88%) as a white solid. EPO <DP n="39"/>
88% Stepl 1; lndole-6-carboxylic acid 1-1 (5.0 g, 31.0 mmol) was dissolved in MeOH (100 ml), acatalytic amount of H2SO4 (1.0 ml) was added and the reaction mixture was stirred atreflux for 16 h. A small amount of solid K2CO3 was added, in order to neutralize theexcess HfeSO^ and stirring was continued at RT for 1h. The reaction mixture wasconcentrated under vacuum to remove the MeOH, diluted with saturated aqueousNaHCO3 (~50 ml_) and extracted with EtOAc (-200 ml). The organic layer waswashed with brine (100 mL), dried over anhydrous MgSO4 and concentrated to dryness. The resulting residue was purified by flash column chromatography, using30% EtOAc in hexane as the eluent, to obtain the pure methyl ester 1-2 (4.78 g, 88%yield).
85% With sulfuric acid; for 16h;Reflux; 1 H-indole-6-carboxylic acid (500 mg)In methanol (10 mL) was added concentrated sulfuric acid (0.1 mL)The mixture was stirred under heating reflux for 16 hours.After the reaction solution was cooled to room temperature, potassium carbonate was added to neutralize it,And the mixture was stirred at room temperature for 1 hour. After distilling off the solvent of the reaction solution under reduced pressure,Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added,The mixture was extracted with ethyl acetate and washed with saturated brine.The organic layer was dried over sodium sulfate,The solvent was evaporated under reduced pressure to obtain a residue,Purification by silica gel column chromatography (hexane-ethyl acetate), Methyl1 H-indole-6-carboxylate462 mg (yield 85%) was obtained
53% With sulfuric acid;Heating / reflux; To a solution of 1H-Indole-6-carboxylic acid (1.500 g, 9.31 mmol) in methanol (50 mL) was added concentrated H2SO4 (550 KL, 10.24 mmol). The mixture was stirred overnight at reflux temperature. The mixture was then neutralised to pH 7 by addition of saturated aqueous NAHC03 and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow powder. The product was recrystallised from heptane/ethyl acetate to give the title compound as GREEN/YELLOW crystals (688 mg, yield = 53%) IH NMR (CDCl3) : 8 3.94 (s, 3H, CH30CO), 6.60 (m, 1H), 7. 37 (t, 1H, J = 4.7 Hz), 7.66 (d, IH, J = 8.2 Hz), 7.82 (dd, 1H, J1 = 8.2 Hz, J2 = 1.0 Hz), 8.18 (s, 1H), 8.73 (s, 1H, NH)
sulfuric acid; for 10h;Steam bath heating; A solution of 1H-indole-6-carboxylic acid (10 g) in methanol (300 mL) was treated with concentrated sulfuric acid (0.5 mL) then heated on a steam bath for 10 hours. The solvent was removed under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution (150 mL) and dichloromethane (150 mL). The aqueous layer was further extracted twice with dichloromethane (150 mL). The combined organics were dried over sodium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluding with a mixture of ethyl acetate and pentane (7:3, v/v) to give the title compound (7.4 g) as a white solid, m.p. 79-81 C. MS: 176(MH+).
With sulfuric acid;Heating / reflux; Indole 6-carboxylic acid (10.00 g, 62 MMOL) was esterified by refluxing overnight in a mixture of MEOH (200 mL) and conc. H2SO4 (1 mL). After cooling, the reaction mixture was poured into sat. aqueous NAHC03 and extracted with EtOAc. The extract was washed with aqueous NAHC03 twice and water. Drying (MGS04) and removal of volatiles gave the desired methyl ester as a brown oil (10.4 g).
With sulfuric acid; at 80℃; General procedure: H2SO4 (98%) (0.5mL) was added to a stirred solution of raw material1 in CH3OH (10mL) at room temperature and the mixture was then stirred for 2-3 h at 80 C. TLC was used to monitor the reaction progress until it was complete. A large amount of ice water was then added to the mixture. A saturated solution of sodium carbonate was used to neutralise the mixture until white solid appeared. After filtering the mixed solution, compounds 2a-h (yield 91-99) were obtained.

  • 22
  • [ 50820-65-0 ]
  • [ 116482-50-9 ]
YieldReaction ConditionsOperation in experiment
70% With N-chloro-succinimide; In ethyl acetate; at 20℃; Methyl 3-chloro- lH-indole-6-carboxylate Methyl indole-6-carboxylate (1.75 g, 10 mmol) and N-chlorosuccinimide (1.33 g, 10 mmol) were mixed in ethyl acetate (200 ml). The reaction mixture was stirred at room temperature overnight. Water was added. The organic phase was washed with 1 M Na2C03 (aq) and brine, dried over MgS04, filtered and concentrated. The remaining solid was washed with water/acetonitrile and collected by filtration. Yield: 1.45 g (70%). White solid. MS (ESI+) m/z 210 [M+H]+. HPLC purity: 100%. 1H NMR (600 MHz, DMSO-d6) δ ppm 11.78 (br. s., 1 H) 8.02 - 8.12 (m, 1 H) 7.79 (d, J=2.75 Hz, 1 H) 7.72 (dd, J=8.39, 1.37 Hz, 1 H) 7.58 (d, J=8.24 Hz, 1 H) 3.86 (s, 3 H).
With N-chloro-succinimide; In dichloromethane; for 3.5h; B. 3-Chloro-1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong>. To a solution of 1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (5.86 g, 33.5 mmol) in 30 ML of CH2Cl2 is added N-chlorosuccinimide (0.58, 4.33 mmol) portionwise over 1.5 hours.The mixture is stirred for 2 h, then diluted with water.The layers are separated and the organic phase is washed with water and saturated NaCl solution.The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound (5.74 g, 27.3 mmol).The crude product is used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.46 (bs, 1H), 8.19 (s, 1H), 7.90 (dd, 1H), 7.69 (d, 1H), 7.36 (d, 1H), 3.97 (s, 3H).
  • 23
  • [ 50820-65-0 ]
  • [ 24424-99-5 ]
  • indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% dmap; In tetrahydrofuran; at 20℃; for 2.33333h; To a solution of 1H-INDOLE-6-CARBOXYLIC acid methyl ester [26.65g, 146 mmol, Intermediate (33) ] and 4- (dimethylarnino) pyridine (230 mg) in anhydrous tetrahydrofuran (490 mL) is added DI-TERT-BUTYL-DICARBONATE (1M in tetrahydrofuran, 150 mL) drop wise over 40 minute periods. Stirred at room temperature for 100 minutes. The solvent is removed in vacuo and the mixture is redissolved in ethyl acetate (400 ML). The ethyl acetate layer is washed with water (20 mL), 0.5 N hydrochloric acid (20 mL), 10% NAHCO3 (20 mL), water (20 mL), brine and dried over sodium sulfate then filtered over 5G silica gel cartridge. The filtrate is reduced in vacuo to solid. The solid is RECRYSTALLIZED from a mixture of ethyl acetate and heptane to give indole-1, 6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester as a white solid (18.53g). The recrystallisation step is repeated to give a second crop of indole-1, 6-dicarboxylic acid 1- tert-butyl ester 6-methyl ester as a white solid (16.3g). A third crop (5.17g) of indole-1, 6- dicarboxylic acid 1-tert-butyl ester 6-methyl ester is obtained from the mother liquor by silica gel chromatography; total yield of IRIDOLE-1, 6-DICARBOXYLIC acid 1-TERT-BUTYL ester 6-methyl ester [40g, 100%, Intermediate (34)] ; 1H NMR (CDCL3) 8 8.886 (1H, s), 7.937 (1H, d), 7.764 (1H), 7.621 (1H, d), 6.636 (1H), 3.972 (3H, s), 1.734 (9H, S) ; LC/MS : 276 (M+H).
99% dmap; In tetrahydrofuran; at 20℃; for 2h; To a solution of <strong>[50820-65-0]methyl 1H-indole-6-carboxylate</strong> (124 g, 708 mmol) in tetrahydrofuran (500 ml) was added 4-dimethylaminopyridine (865 mg, 7 mmol). Then, a solution of di-tert-butyl dicarbonate (156 g, 715 mmol) in tetrahydrofuran (150 ml) was added dropwise at room temperature over about 1 hr, and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound (193 g, yield 99%).1H-NMR (400 MHz, DMSO-d6) δ: 1.65 (9H, s), 3.89 (3H, s), 6.82H, dd, J=3.63, 0.86 Hz), 7.74 (1H, d, J=8.06 Hz), 7.85 (1H, dd, J=8.06, 0.86 Hz), 7.87 (1H, d, J=3.63 Hz), 8.76 (1H, d, J=0.81 Hz).
89% With N,N-dimethylamino-pyridine; In acetonitrile; Example 14 Preparation of 1-[(1,1-dimethylethoxy)carbonyl]-1H-indole-6-carboxylic Acid Methyl Ester A solution of 1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (prepared by the literature method: Brown, F. J.; Cronk, L. A.; Aharony, D.; Snyder, D. W. J. Med. Chem. 1992, 35, 2419-39; 4.55 g, 26.0 mmol), di-tert-butyl dicarbonate (6.00 g, 27.5 mmol) and N,N-dimethylaminopyridine (0.50 g, 4.1 mmol) in acetonitrile (200 mL) was stirred overnight at room temperature. Silica gel was added and the solvent was evaporated. The residue was chromatographed over silica gel (10% ethyl acetate/hexanes) to give 6.33 g (89% yield) of 1-[(1,1-dimethylethoxy)carbonyl]-1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> as a colorless liquid.
  • 24
  • [ 50820-65-0 ]
  • [ 860457-92-7 ]
YieldReaction ConditionsOperation in experiment
98% With NBS; In N,N-dimethyl-formamide; at -60 - 20℃; for 3.33h;Inert atmosphere; Under N2 atmosphere, to an anhydrous DMF solution (10 mL) of <strong>[50820-65-0]methyl 1H-indole-6-carboxylate</strong> (1.00 g, 5.71 mmol) was added dropwise an anhydrous DMF (10 mL) solution of NBS (1.04 g, 5.84 mmol) at -60 oC over 20 min, and stirred and slowly warmed to rt in 3 h. The reaction mixture was worked up by ethyl acetate (100 mL) and water (20 mL, X3), and ethyl acetate layer was concentrated in vacuo and residue was purified by flash chromatography on silica gel with hexanes and ethyl acetate (EA: 0-40%) to give product (1.41 g, 98%).1H NMR (600 MHz, CD3OD) δ 8.15 (s, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.50 (m, 2H), 3.94 (s, 3H).
72.8% With NBS; In N,N-dimethyl-formamide; at -60 - 20℃; To a solution of 17.5 g of methyl 1 H-indole-6-carboxylate dissolved in 200 ml of DMF, cooled at -600C, was added dropwise a solution of 19.6g of NBS in 150 ml of DMF.The reaction mixture was stirred until room temperature was reached, then poured into 2L of an ice/water mixture. The precipitate was filtered then solubilised with 2L of ethyl acetate and washed twice with brine. The solution was dried with Na2SO4 then concentrated "in vacuum."23.5g of brown solid was obtained and re-crystallized using chloroform to give 18.5g of pink crystals of methyl 3-bromo-1 H-indole-6-carboxylate (72.8%).[APCI-MS] m/z: 256.12 (M+H)+, Rt= 3.00 min.
53% With NBS; In N,N-dimethyl-formamide; at 20℃; for 2h; To a stirring solution of methyl lH-indole-6-carboxylate (2 g, 11.42 mmol, 1 eq) in DMF (40 mL), NBS (3.04 g, 17.14 mmol, 1.5 eq) was added then stirred at room temperature for 2 h. The reaction was monitored by crude LCMS/TLC; after completion of the reaction, the mixture was quenched with ice water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with ice water (2 x 30 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ heptane to obtain Int-1 (1.51 g, 53%), as a pale brown solid. MS: m/z=256.1 [M+2]+.
53% With NBS; In N,N-dimethyl-formamide; at 20℃; for 2h; To a stirring solution of methyl lH-indole-6-carboxylate (2 g, 11.42 mmol, 1 eq) in DMF (40 mL), NBS (3.04 g, 17.14 mmol, 1.5 eq) was added then stirred at RT for 2 h. The reaction was monitored by crude LCMS/TLC; after completion of the reaction, the mixture was quenched with ice water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with ice water (2 x 30 mL) and brine (20 mL), dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/heptane to obtain Int-1 (1.51 g, 53%), as a pale brown solid. TLC: 20% EtOAc/Heptane (Ry 0.5). MS: m/z=256.1 [M+2]+.
With bromine; In N,N-dimethyl-formamide; at 20℃; for 0.166667h; (a) 3-Bromo-1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong>. To a solution of <strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (2 g, 11.4 mmol, Acros) in DMF (40 mL) was added dropwise bromine (2 g, 12.5 mmol, Aldrich) with stiiring at room temperature. The reaction mixture was stirred at room temperature for 10 min and quenched with ice-water (200 mL), 0.5% aq. solution of ammonium hydroxide, and 0.1% aq. solution of sodium thiosulphate. The solid precipitate was filtered, washed with water (2*40 mL) and air dried to afford the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 255 (M+1).
With NBS; In N,N-dimethyl-formamide; at -60 - 20℃; for 2h; To a DMF (60 mL) solution of <strong>[50820-65-0]methyl 1H-indole-6-carboxylate</strong> (5.1 g, 29.1 mmol) at -60 C was added a DMF solution (40 mL) of NBS (5.70 g, 32.0 mmol)dropwise. The reaction mixture was stirred for 2 hours while it was warmed up to room temperature. The reaction mixture was then poured into ice water (1 L) and the precipitate formed was collected through via vacuum filtration. The solid was washed with water. The solid was dissolved in ethyl acetate and washed twice with sat. aq. NaC1. The ethyl acetate layer was separated, dried (Na2504), filtered andconcentrated to give the cmde product. The material was carried on without further purification. LCMS (ESI) m/e 254.1 [(M+H), calcd C10H9Br1N1O2, 253.91; LC/MS retention time (method A): IR = 1.63 mm.

  • 25
  • [ 50820-65-0 ]
  • [ 930-30-3 ]
  • [ 863885-65-8 ]
YieldReaction ConditionsOperation in experiment
79% With tin(II) chloride dihdyrate; In isopropyl alcohol; at 20℃; for 16h;Inert atmosphere; To a solution of <strong>[50820-65-0]methyl 1H-indole-6-carboxylate</strong> (17.5 g, 99.9 mmol, 1.0 eq) in i-PrOH (200 mL) was added cyclopent-2-en-1-one (16.4 g, 199.8 mmol, 16.7 mL, 2.0 eq) and SnCl2*2H2O (2.25 g, 9.99 mmol, 831.8 μL, 0.1 eq) under N2. After addition, the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and diluted with DCM (250 mL). The organic layer was separated and washed with H2O (200 mL), brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give compound 03-4-1 (22.4 g, 79% yield).1H NMR (CDCl3, 400 MHz): δ 8.38 (s, 1 H) 8.17 (s, 1 H) 7.84 (d, J=8.8 Hz, 1 H) 7.66 (d, J=8.8 Hz, 1 H) 7.19 (d, J=2.01 Hz, 1 H) 3.97 (s, 3 H) 3.74-3.77 (m, 1 H) 2.77-2.83 (m, 1 H) 2.58-2.59 (m, 1 H) 2.39-2.48 (m, 3 H) 2.15-2.17 (m, 1 H).
70% ytterbium(III) triflate; In acetonitrile; for 16h;Heating / reflux; Step 2:; The methyl ester 1-2 from step 1 (3.31 g, 18.9 mmol) was dissolved in MeCN (50 mL) and a catalytic amount of Yb (OT3 (586 mg, 0.95 mmol) was added. 2-Cyclopenten- 1-one (7.76 mL, 94.5 mmol) was added and the reaction mixture was stirred at reflux for 16 h. The MeCN solvent was removed under vacuum, the residue was re- dissolved in EtOAc (-200 mL) and extracted with aqueous saturated NaHC03 (-100 mL), H2O (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgS04 and concentrated to dryness under vacuum. After purification of the residue by flash column chromatography, using 40% EtOAc in hexane as the solvent gradient, the desired cyclopentanone adduct 1-3 was isolated as isolated as a beige-colored powder (3.4 g, 70% yield).
70% ytterbium(III) triflate; In acetonitrile; for 16h;Heating / reflux; Step 2; The methyl ester 1-2 from step 1 (3.31 g, 18.9 mmol) was dissolved in MeCN (50 ml_)and a catalytic amount of Yb(OTf)3 (586 mg, 0.95 mmol) was added. 2-Cyclopenten-1-one (7.76 ml, 94.5 mmol) was added and the reaction mixture was stirred at reflux for16 h. The MeCN solvent was removed under vacuum, the residue was re-dissolved inEtOAc (-200 ml_) and extracted with aqueous saturated NaHCO3 (-100 ml_), H2O (50ml_) and brine (50 ml_). The organic layer was dried over anhydrous MgSO4 andconcentrated to dryness under vacuum. After purification of the residue by flashcolumn chromatography, using 40% EtOAc in hexane as the solvent gradient, thedesired cyclopentanone adduct 1-3 was isolated as isolated as a beige-coloredpowder (3.4 g, 70% yield).
  • 26
  • [ 50820-65-0 ]
  • [ 98-59-9 ]
  • 1-(toluene-4-sulfonyl)-1H-indole-6-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With potassium carbonate; In butanone; c. Methyl 1-(4-methylphenylsulfonyl)indole-6-carboxylate A solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (15.0 g) in 2-butanone (214 ml) was treated with 4-methylbenzenesulfonylchloride (33 g) and potassium carbonate (47.0 g) and heated to reflux under a nitrogen atmosphere for 18 hours. The hot reaction mixture was filtered, and the filtrate was evaporated to give a solid which was triturated with ether to give methyl 1-(4-methylphenylsulfonyl)indole-6-carboxylate (28.0 g, 99%) as an ivory solid NMR (80 MHz, CDC3): 2.33(s, 3H, ArCH3), 3.95(s, 3H, OCH3), 6.67(dd, 1H, H3-indole), 7.16-7.98(7H, m, Ar), 8.7(m, 1H, H7 -indole)
85% A mixture of methyl lH-indole-6- carboxylate (1.75 g, 10 mmol) and NaH (0.52 g, 13 mmol, 60% in oil) in THF (20 mL) was stirred at r.t. for 30 min, followed by addition of a solution of 4-methylbenzene-l-sulfonyl chloride (2.85 g, 15 mmol) in THF (5 mL). The reaction mixture was stirred at r.t. for another lhr, then quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired product (2.8 g, 85% yield).LCMS: m/z 330 (M+H)+.
The ester from above (10.40 g, 62 MMOL) was dissolved in DMF (80 mL) and the solution cooled in ice. Sodium Hydride (60% oil dispersion, 2.852 g, 71.3 MMOL) was added in small portions and the mixture was stirred at room temperature for 40 min. The reaction mixture was brought back to 0 C and para-toluenesulfonyl chloride (14.49 g, 76 MMOL) was added. The mixture was stirred for 2 h at room temperature. The reaction mixture was then diluted with EtOAc, washed consecutively with 10% citric acid (2 X), NAHCO3 (2 X) and brine. After drying (MGS04), REMOVAL of solvent gave a beige residue that was triturated twice with ether-hexanes (7.7 g). Concentration of mother liquors and trituration of the residue with MEOH gave an additional 5.8 g of the desired tosylated indole.
3.6 g With potassium carbonate; at 80℃; for 16h; To a solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (2.1 g) of 2-pentanone (40 mL), potassium carbonate (6.5 g) and 4-methylbenzenesulfonyl chloride (4.4 g) were added at room temperature, and then the reaction mixture was stirred at 80C for 16 hours. After cooling to room temperature, the insoluble materials were filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, a mixed solvent of ethyl acetate-hexane was added, and the obtained solid was filtered, and washed with hexane to give the titled compound (3.6 g) as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 8.69 (1H, s), 7.93 (1H, dd, J = 8.2, 1.3 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.71 (1H, d, J = 3.7 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.24 (2H, d, J = 8.3 Hz), 6.69 (1H, d, J = 3.4 Hz), 3.97 (3H, s), 2.35 (3H, s).

  • 27
  • aqueous sodium sulfate [ No CAS ]
  • [ 50820-65-0 ]
  • [ 1075-26-9 ]
YieldReaction ConditionsOperation in experiment
82% With hydrogenchloride; diisobutylaluminium hydride; In methanol; toluene; a. 6-Hydroxymethylindole A stirred solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (50 g) (see Example 1, part b) in dry toluene (1 liter), in a three-necked three-liter flask fitted with a mechanical stirrer, thermometer and dropping funnel, was cooled to -70 under an atmosphere of nitrogen, and treated dropwise with a solution of diisobutylaluminum hydride (381 ml of 1.5M solution in toluene) over 50 min. After 2.5 hr a further portion of diisobutylaluminum hydride (25 ml) was added dropwise, and the mixture stirred for a further 30 min. Methanol (100 ml) and saturated aqueous sodium sulfate (100 ml) were added sequentially, at -78. The cooling bath was removed, the reaction allowed to warm to room temperature, and 6M hydrochloric acid (25 ml) was added dropwise. The mixture was filtered through a pad of diatomaceous earth, the filter cake washed with toluene and water, the organic phase separated and washed with water, dried (MgSO4) and evaporated to give 6-hydroxymethylindole (34.2 g, 82%) as an oil which slowly solidified; partial NMR (250 MHz, CDCl3): 1.73(s, 1H, CH2 OH), 4.78(s, 2H, CH2 OH), 6.55(m, 1H, H3 -indole), 8.20(br s, 1H, NH).
  • 28
  • [ 50820-65-0 ]
  • Methyl 3-propionylindole-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% aluminium trichloride; In dichloromethane; propionic acid anhydride; a. Methyl 3-propionylindole-6-carboxylate Propionic anhydride (3.35 g) was added slowly to a stirred suspension of aluminum chloride (6.84 g) in anhydrous methylene chloride (70 ml) under an atmosphere of nitrogen. The mixture was stirred for 15 min, giving a yellow solution. Methyl indole-6-carboxylate (1.5 g) in methylene chloride (12 ml) was added slowly, and the temperature was maintained at approximately 25. After complete addition, the mixture was stirred at the room temperature for 30 min, then poured onto ice (75 ml) and extracted with ethyl acetate. The combined extracts were washed (water (twice), brine), dried (MgSO4) and evaporated to give an off-white solid. The solid was triturated with ether to give methyl 3-propionyl-indole-6-carboxylate (1.73 g, 87%) as a white powder; mp 229-231; NMR (250 MHz, DMSO-d6): 1.12(t, 3H, CH2 CH3), 2.90(q, 2H, CH2 CH3), 3.87(s, 3H, OCH3), 7.80(dd, 1H, H5 -indole), 8.10(s, 1H, H2 -indole), 8.26(d, 1H, H4 -indole), 8.52(d, 1H, H7 -indole), 12.24(br s, 1H, NH).
  • 29
  • [ 908094-01-9 ]
  • [ 1670-82-2 ]
  • [ 50820-65-0 ]
YieldReaction ConditionsOperation in experiment
In diethyl ether; at -15℃; for 1h; Methyl 1H-indole-6-carboxylate; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant.
In diethyl ether; at -15℃; for 1h; Methyl 1H-indole-6-carboxylate.; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using DCM as eluant.
In diethyl ether; at -15℃; for 1h; Methyl 1H-indole-6-carboxylate.; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant.
In diethyl ether; at -15℃; for 1h; Intermediate 19 Methyl 1H-indole-6-carboxylate. An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant.
In diethyl ether; at -15℃; for 1h; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using DCM as eluant.

  • 30
  • [ 50820-65-0 ]
  • [ 108-94-1 ]
  • [ 494799-18-7 ]
YieldReaction ConditionsOperation in experiment
85% Methyl 3-cyclohexyl-1H-indole-6-carboxylate; Cyclohexanone (42.46 mL, 0.40 mol) was added in a single portion to a stirred solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (47.8 g, 0.27 m) in dry dichloromethane (500 mL). The reaction mixture was then cooled to 10 C. and trifluoroacetic acid (63.13 mL, 0.8 m) was added dropwise followed by triethyl silane (174.5 mL, 1.09 m). Upon addition, the temperature was allowed to rise to rt, after which it was stirred for a further 12 h. Dichloromethane (200 mL) was then added and the reaction mixture was washed successively with with 10% sodium bicarbonate solution and brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum. The resultant residuce was purified by flash chromatography on silica (60-120) using hexane-ethyl acetate (9.5:0.5) mixture as eluant. Homogeneous fractions were combined and evaporated to give 60 g of the desired product (85%). Analytical data on this material was consistant with that observed with a sample prepared by the alternative route described above.
85% Methyl 3-cyclohexyl-1H-indole-6-carboxylate.; Cyclohexanone (42.46 mL, 0.40 mol) was added in a single portion to a stirred solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (47.8 g, 0.27 m) in dry dichloromethane (500 mL). The reaction mixture was then cooled to 10 C. and trifluoroacetic acid (63.13 mL, 0.8 m) was added dropwise followed by triethyl silane (174.5 mL, 1.09 m). Upon addition, the temperature was allowed to rise to rt, after which it was stirred for a further 12 h. Dichloromethane (200 mL) was then added and the reaction mixture was washed successively with 10% sodium bicarbonate solution and brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum. The resultant residuce was purified by flash chromatography on silica (60-120) using hexane-ethyl acetate (9.5:0.5) mixture as eluant. Homogeneous fractions were combined and evaporated to give 60 g of the desired product (85%). Analytical data on this material was consistant with that observed with a sample prepared by the alternative route described above.
85% Methyl 3-cyclohexyl-1H-indole-6-carboxylate.; Cyclohexanone (42.46 mL, 0.40 mol) was added in a single portion to a stirred solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (47.8 g, 0.27 m) in dry dichloromethane (500 mL). The reaction mixture was then cooled to 10 C. and trifluoroacetic acid (63.13 mL, 0.8 m) was added dropwise followed by triethyl silane (174.5 mL, 1.09 m). Upon addition, the temperature was allowed to rise to rt, after which it was stirred for a further 12 h. Dichloromethane (200 mL) was then added and the reaction mixture was washed successively with with 10% sodium bicarbonate solution and brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum. The resultant residuce was purified by flash chromatography on silica (60-120) using hexane-ethyl acetate (9.5:0.5) mixture as eluant. Homogeneous fractions were combined and evaporated to give 60 g of the desired product (85%). Analytical data on this material was consistant with that observed with a sample prepared by the alternative route described above.
85% With triethylsilane; trifluoroacetic acid; In dichloromethane; at 10 - 20℃; for 12h;Product distribution / selectivity; Intermediate 20 Methyl 3-cyclohexyl-1H-indole-6-carboxylate. Cyclohexanone (42.46 mL, 0.40 mol) was added in a single portion to a stirred solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (47.8 g, 0.27 m) in dry dichloromethane (500 mL). The reaction mixture was then cooled to 10 C. and trifluoroacetic acid (63.13 mL, 0.8 m) was added dropwise followed by triethyl silane (174.5 mL, 1.09 m). Upon addition, the temperature was allowed to rise to rt, after which it was stirred for a further 12 h. Dichloromethane (200 mL) was then added and the reaction mixture was washed successively with 10% sodium bicarbonate solution and brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum. The resultant residue was purified by flash chromatography on silica (60-120) using hexane-ethyl acetate (9.5:0.5) mixture as eluant. Homogeneous fractions were combined and evaporated to give 60 g of the desired product (85%). Analytical data on this material was consistant with that observed with a sample prepared by the alternative route described above.
85% With triethylsilane; trifluoroacetic acid; In dichloromethane; at 10 - 20℃; for 12h;Product distribution / selectivity; Cyclohexanone (42.46 mL, 0.40 mol) was added in a single portion to a stirred solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (47.8 g, 0.27 m) in dry dichloromethane (500 mL). The reaction mixture was then cooled to 10 C. and trifluoroacetic acid (63.13 mL, 0.8 m) was added dropwise followed by triethyl silane (174.5 mL, 1.09 m). Upon addition, the temperature was allowed to rise to rt, after which it was stirred for a further 12 h. Dichloromethane (200 mL) was then added and the reaction mixture was washed successively with with 10% sodium bicarbonate solution and brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum. The resultant residuce was purified by flash chromatography on silica (60-120) using hexane-ethyl acetate (9.5:0.5) mixture as eluant. Homogeneous fractions were combined and evaporated to give 60 g of the desired product (85%). Analytical data on this material was consistant with that observed with a sample prepared by the alternative route described above.

  • 31
  • [ 3240-94-6 ]
  • [ 50820-65-0 ]
  • [ 1026767-71-4 ]
YieldReaction ConditionsOperation in experiment
[00259] To methyl lH-indole-6-carboxylate (0.5 g, 2.85 mmol) and 4-(2- chloroethyl)morpholine (0.585 g, 3.13 mmol) in anhydrous DMF (5 mL) was added sodium hydride (60% dispersion, 0.342 g, 8.55 mmol) at 0 0C. The reaction mixture was stirred at room temperature for 3 min. and heated at 50 0C for 1.5 h. The reaction mixture was cooled to room temperature and quenched by the slow addition of water (2 mL). The residue was diluted with water (2 mL), methanol (1 mL) and subjected to reverse phase preparative HPLC (YMC S5 20 x 100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were collected, and concentrated using speedVac Plus (SC250DDA) to yield compound a (0.075 g - TFA salt). HPLC retention time (Phenomex Luna 5u C18 ; 4.6 x 30 mm (2 min. gradient); Solvent A = 10% MeOH, 90% H2O, 0.1% TFA; solvent B = 90% MeOH, 10% H2O, 0.1% TFA): 0.87 min. LCMS [M+H]+ 275.
  • 32
  • [ 50820-65-0 ]
  • [ 98-58-8 ]
  • [ 1046151-86-3 ]
YieldReaction ConditionsOperation in experiment
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; To a solution of 500 mg of 1 H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> in 15 ml of DMF 171 mg of NaH (60% in mineral oil) are added. The mixture obtained is stirred for 15 minutes, treated with 789 mg of 4-bromo-benzenesulfonyl chloride, the mixture obtained is stirred overnight at RT and diluted with EtOAc. The organic phase obtained is washed with H2O, dried, and, from the mixture obtained solvent is evaporated. The evaporation residue obtained is subjected to chromatography.1-(4-Bromo-benzenesulfonyl)-1 H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> is obtained.
 

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