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[ CAS No. 50820-65-0 ] {[proInfo.proName]}

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Chemical Structure| 50820-65-0
Chemical Structure| 50820-65-0
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Product Details of [ 50820-65-0 ]

CAS No. :50820-65-0 MDL No. :MFCD00211063
Formula : C10H9NO2 Boiling Point : No data available
Linear Structure Formula :- InChI Key :AYYOZKHMSABVRP-UHFFFAOYSA-N
M.W : 175.18 Pubchem ID :639844
Synonyms :

Calculated chemistry of [ 50820-65-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.1
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 49.58
TPSA : 42.09 ?2

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) : -6.02 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.89
Log Po/w (XLOGP3) : 1.9
Log Po/w (WLOGP) : 1.95
Log Po/w (MLOGP) : 1.38
Log Po/w (SILICOS-IT) : 2.36
Consensus Log Po/w : 1.9

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.5
Solubility : 0.55 mg/ml ; 0.00314 mol/l
Class : Soluble
Log S (Ali) : -2.41
Solubility : 0.687 mg/ml ; 0.00392 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.36
Solubility : 0.0772 mg/ml ; 0.000441 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 50820-65-0 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P305+P351+P338 UN#:
Hazard Statements:H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 50820-65-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

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

[ 50820-65-0 ] Synthesis Path-Downstream   1~14

  • 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).
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