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Product Details of [ 186129-25-9 ]

CAS No. :186129-25-9 MDL No. :MFCD03839859
Formula : C10H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :UHQAIJFIXCOBCN-UHFFFAOYSA-N
M.W : 175.18 Pubchem ID :7015601
Synonyms :

Calculated chemistry of [ 186129-25-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.1
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 50.16
TPSA : 42.23 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.77 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.57
Log Po/w (XLOGP3) : 2.25
Log Po/w (WLOGP) : 1.88
Log Po/w (MLOGP) : 1.38
Log Po/w (SILICOS-IT) : 1.3
Consensus Log Po/w : 1.67

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -2.79
Solubility : 0.284 mg/ml ; 0.00162 mol/l
Class : Soluble
Log S (Ali) : -2.77
Solubility : 0.296 mg/ml ; 0.00169 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.21
Solubility : 1.07 mg/ml ; 0.0061 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.15

Safety of [ 186129-25-9 ]

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

Application In Synthesis of [ 186129-25-9 ]

* 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 [ 186129-25-9 ]

[ 186129-25-9 ] Synthesis Path-Downstream   1~91

  • 1
  • [ 128742-76-7 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
97% With water; sodium hydroxide; In tetrahydrofuran; at 40℃; for 4h; Preparation of 1 -methyl -1 W-indole-5-carboxylic acid To a solution of methyl 1 ~methyj-1H-ndoSe~5-carboxylate (500 mg, 2.64 mmol) in THF/H20 (2 mL/2 mL) was added NaOH (635 mg, 15.9 mmol). The mixture was stirred at 40 C for 4 hours. Then the reaction liquid was concentrated in vacuoio remove most of organic solvent, and H0 (10 mL) was added to the residue. The mixture was acidified (pH 5-6) with HCI (cone.) and the resulting precipitate was collected as the target (450 mg, 97%). LCMS: m/z 176.1 [M+Hf
96% With hydrogenchloride; sodium hydroxide; In THF (50 mL)-MeOH; To a solution of the crude <strong>[128742-76-7]methyl 1-methylindole-5-carboxylate</strong> in THF (50 mL)-MeOH (50 mL) was added a 6N NaOH solution (5.4 mL), and the mixture was stirred at room temperature for 144 hours. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate, and thereto was added a 6N aqueous hydrochloric acid solution to adjust the pH value thereof to pH=5-6. The mixture was extracted twice with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 1-methyl-1H-indol-5-carboxylic acid (1.08 g, 96%). 1H NMR (DMSO-d6, 400 MHz) delta 12.42 (brs, 1H,), 8.23 (d, 1H, J=1.2 Hz), 7.76 (dd, 1H, J=8.6, 1.2 Hz), 7.50 (d, 1H, J=8.6 Hz), 7.43 (d, 1H, J=3.1 Hz), 6.57 (dd, 1H, J=3.1, 0.7 Hz), 3.82 (s, 3H).
96% With hydrogenchloride; sodium hydroxide; In THF (50 mL)-MeOH; To a solution of the crude <strong>[128742-76-7]methyl 1-methylindole-5-carboxylate</strong> in THF (50 mL)-MeOH (50 mL) was added a 6N NaOH solution (5.4 mL), and the mixture was stirred at room temperature for 144 hours. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate, and thereto was added a 6N aqueous hydrochloric acid solution to adjust the pH value thereof to pH=5-6. The mixture was extracted twice with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 1-methyl-1H-indol-5-carboxylic acid (1.08 g, 96 %). 1H NMR (DMSO-d6, 400MHz) delta 12.42 (brs, 1H,), 8.23 (d, 1H, J=1.2Hz), 7.76 (dd, 1H, J=8.6, 1.2Hz), 7.50 (d, 1H, J=8.6Hz), 7.43 (d, 1H, J=3.1Hz), 6.57 (dd, 1H, J=3.1, 0.7Hz), 3.82 (s, 3H).
94% To a stirred solution of methyl L-METHYL-LH-INDOLE-5-CARBOXYLATE (500 mg, 2.65 mmol) in MEOH (5 mL) is added sodium hydroxide (20 mL of a 2.5% aqueous solution). The mixture is heated at 80C for 1.5 h and MEOH is removed in vacuo. The remaining aqueous solution is acidified with 1 N aqueous HC1 to pH = 2. The resulting precipitate is collected by filtration, washed with water and dried in vacuo to afford 1-METHYL-LH-INDOLE-5-CARBOXYLIC acid as a white solid (437 mg, 94%) : LH NMR (400 MHz, DMSO-d6) 8 12. 44,8. 23,7. 75,7. 50,7. 44,6. 57,3. 83.
In sodium hydroxide; ethanol; Step B. 1-Methyl-indole-5-carboxylic Acid A solution of <strong>[128742-76-7]1-methyl-indole-5-carboxylic acid methyl ester</strong> of Step A (2.5 g, 13.2 mmol) in ethanol (40 mL) containing 2.5N aqueous NaOH (3:1, v/v) was heated at reflux for one hour. The reaction mixture was concentrated in vacuo, and the residue partitioned between diethyl ether and 1N HCl. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dryness to provide the title compound as an off-white solid (1.82 g). NMR (DMSO-d6, 300 MHz): delta 3.82 (s, 3H), 6.58 (dd, 1H), 7.42 (d, 1H), 7.48 (d, 1H), 7.75 (d, 1H), 8.22 (s, 1H), 12.38 (broad s, 1H).
In sodium hydroxide; ethanol; Step B. 1-Methyl-indole-5-carboxylic acid A solution of <strong>[128742-76-7]1-methyl-indole-5-carboxylic acid methyl ester</strong> of Step A (2.5 g, 13.2 mmol) in ethanol (40 mL) containing 2.5N aqueous NaOH (3:1, v/v) was heated at reflux for one hour. The reaction mixture was concentrated in vacuo, and the residue partitioned between diethyl ether and 1N HCl. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dryness to provide the title compound as a off-white solid (1.82 g). NMR (DMSO-d6, 300 MHz): delta 3.82 (s, 3H), 6.58 (dd, 1H), 7.42 (d, 1H), 7.48 (d, 1H), 7.75 (d, 1H), 8.22 (s, 1H), 12.38 (broad s, 1H)
To a solution of the crude product 1-37 in THF (80 mL) was added 80 mL of a 1 M LiOH aqueous solution. The mixture was stirred at 500C for 24 hours and then diluted with diethyl ether. After the mixture was then extracted twice with a saturated NaHCtheta3 aqueous solution, 6 M HCl was added to the combined aqueous layers to adjust the pH to 1. The aqueous layer was then extracted with ethyl acetate. The combined ethyl acetate layer was dried over Na2SO4, filtered, and concentrated to give compound 1-38 (4.72 g, 87%). 1H NMR (CDCl3) delta 8.49 (s, IH), 8.01-7.98 (dd, J = 8.4 Hz, 1.5 Hz, IH), 7.38-7.35 (d, J = 8.7 Hz, IH), 7.14-7.13 (d, J = 3.0 Hz, IH), 6.63 (d, J = 3.0 Hz, IH), 3.84 (s, 3H). ESI-MS (M+H+) = 176.
To the solution of 53 (4.90 g, 25.89 mmol) in THF/H2O was added 1N NaOH and the resulting mixture was heated at reflux for 60 min. The reaction mixture was cooled to 0 C., acidified with 1N HCl to ca. pH=3, and the mixture was partitioned between H2O and EtOAc and the combined organic layers were dried (MgSO4), filtered and concentrated to afford 4.25 g of 1-methyl-1H-indole-5-carboxylic acid (55).
With sodium hydroxide; In ethanol; water; for 1h;Heating / reflux; Step B. 1-Methyl-indole-5-carboxylic acid. A solution of <strong>[128742-76-7]1-methyl-indole-5-carboxylic acid methyl ester</strong> of Step A (2.5 g, 13.2 mmol) in ethanol (40 mL) containing 2.5 N aqueous NaOH (3:1, v/v) was heated at reflux for one hour. The reaction mixture was concentrated in vacuo, and the residue partitioned between diethyl ether and 1N HCl. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dryness to provide the title compound as a off-white solid (1.82 g). NMR (DMSO-d6, 300 MHz): delta 3.82 (s, 3H), 6.58 (dd, 1H), 7.42 (d, 1H), 7.48 (d, 1H), 7.75 (d, 1H), 8.22 (s, 1H), 12.38 (broad s, 1H).

  • 2
  • 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol acetic acid salt [ No CAS ]
  • [ 186129-25-9 ]
  • 1-methyl-1H-indole-5-carboxylic acid N-[2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% Stage #1: 1-methyl-1H-indole-5-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol acetic acid salt With dmap In N,N-dimethyl-formamide for 18h; Further stages.;
  • 3
  • C9H8ClMgN [ No CAS ]
  • [ 124-38-9 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
48% In tetrahydrofuran at 1℃; for 0.0833333h;
  • 4
  • [ 124-38-9 ]
  • (1-methyl-1H-indol-5-yl)magnesium bromide [ No CAS ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
84% In tetrahydrofuran at 1℃; for 0.0833333h;
  • 5
  • ethyl N-methyl-1H-indole-5-carboxylate [ No CAS ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In ethanol; water for 8h; Heating;
With lithium hydroxide In tetrahydrofuran; methanol; water at 20 - 30℃; 2.1.3. General procedure for the synthesis of N-substituted-ethyl-indole-5-carboxylic acid (3a-o) General procedure: To a 100 ml single neck RB flask, N-substituted-ethyl-indole-5-carboxylate(1 eq), THF: MeOH: H2O (1:1:0.5) (20 V) were added and the reaction mass stirred for 5mins at 20-30 °C. Lithium hydroxide (5.0 eq)added and stirred for further 4-6 h at 20-30 °C until the reaction completion confirmed by TLC/LCMS. Upon the reaction completion,the reaction mass was concentrated under vacuum and the residual material was diluted with 20 V of water. The pH was adjusted to 3-4using 3 N HCI and the product was extracted using ethyl acetate(2×15 V). The separated ethyl acetate layer washed with water (10 V),dried over anhydrous sodium sulfate, and concentrated under vacuum.The obtained products (3a-o) dried thoroughly under vacuum and taken for coupling reaction without further purification.
  • 6
  • [ 186129-25-9 ]
  • 1-methyl-1H-indole-5-carbonyl azide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With diphenyl phosphoryl azide; triethylamine In benzene at 20℃; for 1h;
  • 7
  • [ 1011-65-0 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: NaH / dimethylformamide / 1 h / 0 °C 1.2: dimethylformamide / 2.5 h / 0 - 20 °C 2.1: NaOH / methanol; H2O / 8 h / Heating
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 °C 1.2: 0 - 50 °C 2.1: water; sodium hydroxide / tetrahydrofuran / 4 h / 40 °C
  • 9
  • [ 186129-25-9 ]
  • [ 884507-16-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine; diphenylphosphorazidate / benzene / 1 h / 20 °C 2: chlorobenzene / 1 h / Heating
  • 10
  • [ 186129-25-9 ]
  • 8,8-dimethoxy-6-dimethoxymethyl-3-methylpyrrolo[3,2-e]indol-7(3H,6H,8H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine; diphenylphosphorazidate / benzene / 1 h / 20 °C 2: chlorobenzene / 1 h / Heating 3: 53 mg / chlorobenzene / 0.25 h / Heating
  • 11
  • [ 186129-25-9 ]
  • 1-(bis(propylthio)methyl)-6-methyl-3,3-bis(propylthio)pyrrolo[2,3-e]indol-2(1H,3H,6H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine; diphenylphosphorazidate / benzene / 1 h / 20 °C 2: chlorobenzene / 1 h / Heating 3: 62 mg / benzene / 2 h / Heating
  • 12
  • [ 10075-52-2 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: magnesium / tetrahydrofuran / 0.5 h / 120 °C / microwave irradiation 2: 84 percent / tetrahydrofuran / 0.08 h / 1 °C
  • 13
  • [ 112398-75-1 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: magnesium; 1,2-dibromoethane / tetrahydrofuran / 0.5 h / 200 °C / microwave irradiation 2: 48 percent / tetrahydrofuran / 0.08 h / 1 °C
  • 14
  • [ 186129-25-9 ]
  • 1-methyl-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-oxazol-2-yl]-1<i>H</i>-indole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 1-hydroxybenzotriazole; Et3N; EDCI / dimethylformamide / 0.25 h / 20 °C 1.2: 50 percent / 4-(N,N-dimethylamino)pyridine / dimethylformamide / 18 h 2.1: 52 percent / [(methoxycarbonyl)sulfamoyl]triethylammonium hydroxide / tetrahydrofuran / 1 h / Heating
  • 15
  • [ 186129-25-9 ]
  • [ 949899-71-2 ]
YieldReaction ConditionsOperation in experiment
With 2,4,6-trichlorobenzoyl chloride; triethylamine In tetrahydrofuran 1.C (5H-10,11-Dihydro-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(1-methyl-1H-indol-5-yl)-methanone Step C. (5H-10,11-Dihydro-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(1-methyl-1H-indol-5-yl)-methanone. Under anhydrous conditions, 2,4,6-trichlorobenzoyl chloride was added in one portion to a stirred solution of an equimolar amount of 1-methyl indole 5-carboxylic acid (0.327 g, 1.87 mmol) of Step B and triethylamine in dry tetrahydrofuran (0.1-0.3 molar). Upon completion of anhydride formation, the precipitate was filtered off and washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the residue was dissolved in dichloromethane and added to a solution of equimolar amounts of the 10,11-dihydro-5H-pyrrolo[2,1c][1,4]-benzodiazepine (0.514 g, 2.8 mmol) and 4-dimethylamino pyridine in dichloromethane. Stirring was continued until the reaction was complete (TLC). The mixture was diluted with dichloromethane, washed sequentially with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. The solvent was evaporated, and the crude product was flash chromatographed (silica gel Merck-60, hexane/ethyl acetate 4:1) to provide pure title compound as a white solid (0.160g), m.p. 172-173° C., after recrystallization from diethyl ether. NMR (DMSO-d6, 400 MHz): δ 3.71 (s, 3H), 5.1 (broad s, 2H), 5.32 (broad s, 2H), 5.92 (m, 2H), 6.35 (m, 1H), 6.81 (m, 2H), 7.03 (m, 2H), 7.11 (m, 1H), 7.22 (d, 1H), 7.30 (d, 1H), 7.45 (dd, 1H), 7.55 (s, 1H); MS (EI, m/z): 341 [M]+, 183, 158; Anal. Calcd. For C22H19N3O: C, 77.40; H, 5.61; N, 12.31. Found: C, 76.87; H, 5.69; N, 12.42.
With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In dichloromethane for 0.5h;
  • 16
  • [ 515881-16-0 ]
  • [ 186129-25-9 ]
  • 5-[[4-[4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1-piperidinyl]-4-methyl-1-piperidinyl]carbonyl]-1-methyl-1H-indole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; HATU In DMF (N,N-dimethyl-formamide) at 20℃; for 16h; 56 Example 56: Preparation of 5-[[4-[4-[(Z)-(4-Bromophenyl)(ethoxyimino)methyl]-1-piperidinyl]-4-methyl-1-piperidinyl]carbonyl]-1-methyl-1H-indole To a stirred solution OF 4- [ (Z)- (4-BROMOPHENYL) (ethoxyimino) methyl]-1-(4-methyl-4- piperidinyl) piperidine (50 mg, 0.12 MMOL), 1-METHYL-1 H-INDOLE-5-CARBOXYLIC acid (23 mg, 0.13 MMOL), and Et3N (24.3 mg, 0.24 MMOL) in DMF (2 mL), HATU (60.8 mg, 0.16 MMOL) was added at room temperature. After 16 h the mixture was poured into ice water (10 mL), and solid was collected by filtration. The solid was dissolved in CH2CI2, and purified by preparative TLC to afford the title COMPOUND. H NMR (CDCI3, 400MHZ) 8 0.93 (s, 3H), 1.3 (t, 3H), 1.34-2. 0 (m, 8H), 2.08-2. 3 (m, 2H), 2.7-3. 1 (m, 2H), 3.1-3. 4 (m, 2H), 3.4-3. 68 (m, 2H), 3.8 (s, 3H), 3.86-4. 1 (m, 1H), 4.12-4. 24 (q, 2H), 6. 48-6. 54 (m, 1H), 7. 08-7.14 (d, 1H), 7.2-7. 34 (m, 4H), 7.44-7. 54 (m, 2H), 7.66-7. 74 (m, 1 H).
YieldReaction ConditionsOperation in experiment
72% With water; sodium hydroxide In tetrahydrofuran; methanol at 20℃; for 18h; 54-2 Preparation Example 1-2: synthesis of 1-isopropyl-1H-indole-5-carboxylic acid General procedure: The compound (1.1 g, 5.06 mmol) obtained from Preparation Example 1-1 was dissolved in a mixed solution of tetrahydrofuran and methanol (2/1, 20 mL), and 1N sodium hydroxide aqueous solution (10 mL, 10.12 mmol) was slowly added dropwise thereto. The mixture was stirred for 18 hours at room temperature, added with 1N hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with brine, dried with anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain the title compound (900 mg, 88%).[330] NMR: 1H-NMR (400HMz, CDCl3); δ 8.49 (s, 1H), 7.98(dd, 1H), 7.41(d, 1H), 7.30(d, 1H), 6.64(d, 1H), 4.72(m, 1H), 1.56(d, 6H)
  • 18
  • [ 186129-25-9 ]
  • [ 380922-37-2 ]
YieldReaction ConditionsOperation in experiment
98% With sodium cyanoborohydride; acetic acid at 20℃; for 0.333333h; 36 To a solution of compound 1-38 (0.05 g, 1 eq.) in HOAc (2 mL) was addedNaCNBH3 (0.04 g, 2 eq.). The mixture was stirred at room temperature for 20 minutes. After HOAc was removed, the mixture was diluted with H2O (5 mL) and ethyl acetate (10 mL). The mixture was then washed twice with a saturated NaHCO3 aqueous solution, extracted with ethyl acetate (20 mL), dried over Na2SO4, filtered, and concentrated to give compound 1-39 (0.05 g, 98%). 1H NMR (CDCl3) δ 7.78- 7.75 (d, J = 8.1 Hz, IH), 7.63 (s, IH), 6.35-6.32 (d, J = 8.4 Hz, IH), 3.45-3.39 (t, J = 8.4 Hz, 2H), 2.91 (t, J = 8.4 Hz, 2H), 2.79 (s, 3H). ESI-MS (M+H+) = 178.
65% With triethylsilane; trifluoroacetic acid In dichloromethane at 0 - 20℃; for 2h; 55 (Intermediate Example 55) 1-Methyl-2,3-dihydro-1H-indole-5-carboxylic acid Dichloromethane (2ml) andtriethylsilane (1ml) were added to 1-methyl-1H-indole-5-carboxylic acid (100 mg). The mixture was cooled to 0°C, trifluoroacetic acid (1 ml) was added dropwise thereto, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and precipitate was collected by filtration. The precipitate was washed with ether and dried under reduced pressure to give the title compound (66 mg, Y.: 65%). 1H NMR; (DMSO-d6) δ (ppm): 2.7 (3H, s), 2.9 (2H, t), 3.4 (2H, t), 6.4 (1H, d), 7.5 (1H, s), 7.6 (1H, d). ESI/MS (m/z): 178 (M+H)+, 176 (M-H)-.
  • 19
  • [ 1670-81-1 ]
  • Methyl trifluoromethane sulfonate [ No CAS ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide 22.i i) i) Preparation of N-methylindol-5-carboxylic acid 0.1 g of indol-5-carboxylic acid was mixed with 2 equivalents of methyl trifluoromethane sulfonate in 1 ml DMF at room temperature. After 5 h the solvent was evaporated and 1H-NMR was recorded: 1H-NMR (250 MHz, DMSO-d6) δ 2.76 (s, 3H), 6.57 (board s, 1H), 7.46-7.50 (m, 2H), 7.75 (dd, 1H), 8.23-8.29 (m, 2H), 11.56 (broad s, 1H). ii(Preparation of title compound. N-methylindol-5-carboxylic acid and (1S,2S)-N-(cis-2-(6-fluoro-2-hydroxy-3-propionylphenyl)-cyclopropyl)-N'-(5-bromopyrid-2-yl)-urea from Example 10 were condensed using the method described in Example 12 to obtain the title product as the hydrochloride salt. 1H-NMR (250 MHz, CDCl3) δ 1.08 (t, 3H), 1.15-1.25 (m, 1H), 1.39-1.50 (m, 1H), 1.92-2.08 (m, 1H), 2.89 (q, 2H), 2.90 (s, 3H), 3.20-3.35 (m, 1H), 6.55 (broad s, 1H), 6.65 (broad d, 1H), 7.11 (t, 1H), 7.20-7.29 (m, 2H), 7.41 (dd, 1H), 7.72-7.83 (m, 2H), 7.95 (dd, 1H), 8.51 (broad s, 1H), 9.25 (broad s, 1H), 9.43 (broad s, 1H).
  • 20
  • ethyl acetate n-hexane [ No CAS ]
  • [ 4136-95-2 ]
  • [ 16287-36-8 ]
  • [ 186129-25-9 ]
  • [ 287957-64-6 ]
YieldReaction ConditionsOperation in experiment
With N,N-dimethylamino-pyridine; triethylamine In dichloromethane 1.C Step C. Step C. (5,11-Dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-(1-methyl-1H-indol-5-yl)-methanone Under anhydrous conditions, 2,4,6-trichlorobenzoyl chloride was added in one portion to a stirred solution of equimolar amounts of 1-methyl-indole-5-carboxylic acid (0.327 g, 1.87 mmol) of Step B, and triethylamine in dry dichloromethane (25-50 mL). When anhydride formation was complete, the 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (0.519 g, 2.8 mmol) and N,N-dimethylaminopyridine were added to the clear solution. Stirring was continued until the reaction was complete (TLC). The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Removal of the solvent and flash-chromatography of the residue (on silica gel Merck-60, hexane-ethyl acetate 4:1) provided the title compound as a white solid (0.260 g), m.p. 147-148° C., upon recrystallization from diethyl ether. NMR (DMSO-d6, 400 MHz): δ 3.70 (s, 3H), 4.06 (broad d, 1H), 5.62 (broad d, 1H), 6.30 (s, 1H), 6.48 (t, 1H), 6.50 (d, 1H), 6.73 (m, 1H), 6.89 (d, 1H), 7.05 (t, 1H), 7.20 (d, 1H), 7.33 (m, 2H), 7.43 (s, 1H), 7.51 (broad s, 1H), 8.14 (m, 1H), 9.56 (s, 1H); MS (El, m/z): 354 [M]+, 158.
  • 21
  • (S)-(+)-1-isopropyl-1-methyl-prop-2-ynylamine hydrochloride [ No CAS ]
  • [ 186129-25-9 ]
  • [ 1029431-04-6 ]
YieldReaction ConditionsOperation in experiment
6% Stage #1: (S)-(+)-1-isopropyl-1-methyl-prop-2-ynylamine hydrochloride; [7-((S)-2-azido-hexanolylamino)-4-methyl-2-oxo-2H-chromen-3-yl]acetyl-Wang resin With copper(l) iodide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 48h; Stage #2: 1-methyl-1H-indole-5-carboxylic acid With 2,4,6-trimethyl-pyridine; bis(trichloromethyl) carbonate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Stage #3: With chlorotriisopropylsilane; trifluoroacetic acid In dichloromethane; water at 20℃; for 1h; Further stages.;
  • 22
  • [ 882678-96-8 ]
  • [ 186129-25-9 ]
  • C23H27BN2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; 15.3 To a solution of 55 (0.608 g, 3.474 mmol, CASRN 186129-25-9) and DMF was added 14a (0.27 g, 1.158 mmol), DIPEA (0.60 mL, 3.474 mmol)) and HATU (0.484 g, 1.274 mmol). The reaction mixture was stirred at RT over night. The reaction mixture was partitioned between EtOAc and H2O, the EtOAc phase was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with 42% EtOAc/hexane to afford 236 mg of 59.
  • 23
  • [ 1670-81-1 ]
  • [ 74-88-4 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
84% General procedure: Indole-5-carboxaldehyde or indole-5-carboxylic acid (1 or 18, 1.0mmol) was dissolved in anhydrous DMF under magnetic stirring, and the temperature was set to 0C. To this solution, 1.5mmol of NaH was added portionwise and the mixture was allowed to react for 30min. Then, 1.5mmol of alkyl iodide [methyl iodide or propyl iodide, or 4-[phenyl]iodomethylbenzene] in DMF was added dropwise and the reaction was warmed to room temperature and maintained under stirring for further 12h. Then, reaction was quenched by 10% aqueous solution of citric acid and washed with brine. Organic layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. Crude products were purified by column chromatography using n-hexane/ethyl acetate (4:1 v:v) as mobile phase, to obtain intermediate compounds 2, 3, 18a and 41 with 89, 92, 90 and 78% of yields respectively.
  • 25
  • [ 186129-25-9 ]
  • [ 1201323-70-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-chloro-1-(dimethylamino)-2-methyl-1-propene / dichloromethane / 0.5 h 2: pyridine / 0.5 h 3: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 165 °C
  • 26
  • [ 1584114-32-8 ]
  • [ 186129-25-9 ]
  • [ 1608117-95-8 ]
YieldReaction ConditionsOperation in experiment
With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 6h;
  • 27
  • [ 72084-11-8 ]
  • [ 186129-25-9 ]
  • [ 1608117-98-1 ]
YieldReaction ConditionsOperation in experiment
With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 6h;
  • 28
  • [ 1608117-92-5 ]
  • [ 186129-25-9 ]
  • [ 1608118-01-9 ]
YieldReaction ConditionsOperation in experiment
With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 6h;
  • 29
  • (S<SUB>S</SUB>)-2-methyl-N-(2,2,2-trifluoroethylidene)-propane-2-sulfinamide [ No CAS ]
  • [ 186129-25-9 ]
  • [ 1620835-87-1 ]
  • [ 1620835-99-5 ]
YieldReaction ConditionsOperation in experiment
54 % de With boron trifluoride diethyl etherate In dichloromethane at 0℃; for 10h; Overall yield = 90 %; Overall yield = 338 mg;
  • 30
  • [ 1338563-14-6 ]
  • [ 186129-25-9 ]
  • C20H21N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate
  • 31
  • [ 5321-49-3 ]
  • [ 186129-25-9 ]
  • (1-methyl-1H-indol-5-yl)(4-phenethylpiperazin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 40℃; Preparation of Compound 4025, (1-methyi-1W-indol-5-yl){4-p enethylpiperazin-1- yl)methanone Preparation of Compound 4025, (1-methyi-1W-indol-5-yl){4-p enethylpiperazin-1- yl)methanone To a solution of 1 -methyl-1 W-indoie-S-carboxylic acid (88 mg, 0.5 mmol) and -phenethylpiperazine (95 mg, 0.5 mmol) in DMF (5 mL) was added EDCI (192 mg, 1 mmol). The mixture was stirred at 40 overnight. The reaction mixture was partitioned between EtOAc and water. Th organic layer was washed with water and brine, then dried, concentrated and purified by prep-TLC (MeOH/DCM=1/2Q) to afford a solid (105 mg, 63%). 1H N R (400 MHz, CDCI3): δ 7.75 (br s, 1 H), 7.35-7,29 (m, 4H), 7.25-7.23 (m, 3H), 7.13 (d, J = 3.2 Hz, 1 H), 6.55 (d, J = 3.2 Hz, 1 H), 3.82 (s, 3H), 3.71 (br s, 4H), 2.87- 2.82 (m, 2H), 2,69-2.65 (m, 2H), 2,58 (br s, 4H). LCMS: m/z 348.2 [M+H]+
  • 32
  • [ 186129-25-9 ]
  • [ 916518-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; dmap / dichloromethane / 2 h / 20 °C / Inert atmosphere 1.2: 3 h / 40 °C / Inert atmosphere 2.1: sodium t-butanolate; 1,3-dicyclohexyl-1H-imidazol-3-ium chloride; nickel(II) acetate tetrahydrate; potassium phosphate / toluene; cyclohexane / 24 h / 150 °C / Inert atmosphere
  • 33
  • [ 24424-99-5 ]
  • [ 593-51-1 ]
  • [ 186129-25-9 ]
  • tert-butyl methyl(1-methyl-1H-indole-5-carbonyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% Stage #1: methylamine hydrochloride; 1-methyl-1H-indole-5-carboxylic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: di-<i>tert</i>-butyl dicarbonate With dmap In acetonitrile at 40℃; for 3h; Inert atmosphere;
  • 34
  • [ 696-62-8 ]
  • [ 186129-25-9 ]
  • 4,6-bis(4-methoxyphenyl)-1-methyl-1H-indole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With C30H54N6Ru(2+)*2BF4(1-); potassium perfluoro-tert-butoxide; potassium carbonate at 140℃; for 24h; Glovebox; Inert atmosphere;
  • 35
  • [ 591-50-4 ]
  • [ 186129-25-9 ]
  • 1-methyl-4,6-diphenyl-1H-indole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With C30H54N6Ru(2+)*2BF4(1-); potassium perfluoro-tert-butoxide; potassium carbonate at 140℃; for 24h; Glovebox; Inert atmosphere;
  • 36
  • [ 637-87-6 ]
  • [ 186129-25-9 ]
  • 4,6-bis(4-chlorophenyl)-1-methyl-1H-indole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With C30H54N6Ru(2+)*2BF4(1-); potassium perfluoro-tert-butoxide; potassium carbonate at 140℃; for 24h; Glovebox; Inert atmosphere;
  • 37
  • [ 589-87-7 ]
  • [ 186129-25-9 ]
  • 4,6-bis(4-bromophenyl)-1-methyl-1H-indole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With C30H54N6Ru(2+)*2BF4(1-); potassium perfluoro-tert-butoxide; potassium carbonate at 140℃; for 24h; Glovebox; Inert atmosphere;
  • 38
  • [ 455-13-0 ]
  • [ 186129-25-9 ]
  • 1-methyl-4,6-bis(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With C30H54N6Ru(2+)*2BF4(1-); potassium perfluoro-tert-butoxide; potassium carbonate at 140℃; for 24h; Glovebox; Inert atmosphere;
  • 39
  • [ 186129-25-9 ]
  • 6-chloro-2-(1-methyl-1H-indol-5-yl)benzo[d]thiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: Lawessons reagent / toluene / 80 °C / Inert atmosphere 3: palladium dichloride; copper(l) iodide; tetrabutylammomium bromide / dimethyl sulfoxide; 1-methyl-pyrrolidin-2-one / 2 h / Inert atmosphere; Heating
  • 40
  • [ 186129-25-9 ]
  • 6-bromo-2-(1-methyl-1H-indol-5-yl)benzo[d]thiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: Lawessons reagent / toluene / 80 °C / Inert atmosphere 3: palladium dichloride; copper(l) iodide; tetrabutylammomium bromide / dimethyl sulfoxide; 1-methyl-pyrrolidin-2-one / 2 h / Inert atmosphere; Heating
  • 41
  • [ 186129-25-9 ]
  • N-(4-chlorophenyl)-1-methyl-1H-indole-5-carbothioamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: Lawessons reagent / toluene / 80 °C / Inert atmosphere
  • 42
  • [ 186129-25-9 ]
  • N-(4-bromophenyl)-1-methyl-1H-indole-5-carbothioamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: Lawessons reagent / toluene / 80 °C / Inert atmosphere
  • 43
  • [ 106-47-8 ]
  • [ 186129-25-9 ]
  • N-(4-chlorophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
  • 44
  • [ 106-40-1 ]
  • [ 186129-25-9 ]
  • N-(4-bromophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
  • 45
  • [ 6638-79-5 ]
  • [ 186129-25-9 ]
  • N-methoxy-N,1-dimethyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-methyl-1H-indole-5-carboxylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With pyridine at 20℃; for 18h; Oxalyl chloride (1.55 mL, 18.3 mmol) was added to a suspensionof the above acid (2.48 g, 15.3 mmol) in DCM (100 mL, anhydrous)and DMF (0.05 mL, 0.64 mmol) at 20 C. The mixture wasstirred at 20 C for 1 h to give a colourless solution which wascooled to 0 C. N,O-Dimethylhydroxylamine hydrochloride (1.64g, 16.8 mmol) and pyridine (3.71 mL, 45.9 mmol) were addedsequentially and the mixture was stirred at 20 C for 18 h, thenpartitioned between EtOAc and sat. aq. NaHCO3. Column chromatographywith 95:5 DCM:EtOAc gave N-methoxy-N-methylbenzofuran-5-carboxamide (2.28 g, 73%) as a pale brown oil. 1H NMR(CDCl3) d 7.99 (d, J = 1.4 Hz, 1H), 7.65-7.69 (m, 2H), 7.52 (dt, J =8.6, 0.6 Hz, 1H), 6.82 (dd, J = 2.2, 0.9 Hz, 1H), 3.56 (s, 3H), 3.39 (s,3H). Found: [M+H] = 206.2.
  • 46
  • [ 186129-25-9 ]
  • 3-(dimethylamino)-1-(1-methyl-1H-indol-6-yl)propan-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 1 h / 20 °C 1.2: 18 h / 20 °C 2.1: tetrahydrofuran / 1 h / 0 °C 2.2: 1 h / 20 °C
  • 47
  • [ 186129-25-9 ]
  • C32H33BrN2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 1 h / 20 °C 1.2: 18 h / 20 °C 2.1: tetrahydrofuran / 1 h / 0 °C 2.2: 1 h / 20 °C 3.1: diisopropylamine; n-butyllithium / tetrahydrofuran; cyclohexane / 1.5 h / -78 - -40 °C / Inert atmosphere 3.2: 4 h / -78 °C / Inert atmosphere
  • 48
  • [ 597555-55-0 ]
  • [ 186129-25-9 ]
  • tert-butyl {(1S,2S)-2-[(1-methyl-1H-indole-5-carbonyl)amino]-2,3-dihydro-1H-inden-1-yl}carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: 1-methyl-1H-indole-5-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h; Stage #2: tert-butyl [(1S,2S)-2-amino-2,3-dihydro-1H-inden-1-yl]-carbamate In dichloromethane at 20℃;
  • 50
  • [ 371-40-4 ]
  • [ 186129-25-9 ]
  • N-(4-fluorophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; 5.3 General method for coupling reactions. Synthesis of 1-alkyl-1H-indole-5-carboxamide derivatives (19, 32-34, and 42) General procedure: To a solution of 1-alkyl-1H-indole-5-carboxylic acids 18a or 41 (1.0mmol) in dichloromethane, different aromatic or aliphatic amines (1.2mmol), PyBop (1.2mmol) and DIPEA (2.4mmol) were successively added. Stirring was continued at room temperature for 12h. Afterward, the reaction mixture was diluted with dichloromethane (20mL), and the resulting solution was washed successively with 10% citric acid (2×25mL), 10% NaHCO3 (2×25mL), and water (2×25mL), dried over Na2SO4 and evaporated to dryness. Flash chromatography of the residues, using a mixture of ethyl acetate/n-hexane as eluent systems, yielded, in each case, the corresponding 5-carboxamide indole derivatives in 56-64% of yield.5.3.1 10 N-(4-fluorophenyl)-1-methyl-1H-indole-5-carboxamide (19) (0027) Yield 56%. 1H NMR (400MHz, CD3OD) δ; 3.88 (s, 3H, CH3); 6.60 (d, 1H, aryl, J=4.0Hz); 7.09-7.14 (m, 2H, aryl); 7.30 (d, 1H, aryl, J=4.0Hz); 7.50 (d, 1H, aryl, J=12.0Hz), 7.69-7.74 (m, 2H, aryl); 7.80 (d, 1H, aryl, J=4.0Hz); 8.24 (s, 1H, aryl). HR-MS m/z calcd for C16H14FN2O [(M+H)]+: 269.1085 found 269.1090.
  • 51
  • [ 106-49-0 ]
  • [ 186129-25-9 ]
  • 1-methyl-N-(4-tolyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; 5.3 General method for coupling reactions. Synthesis of 1-alkyl-1H-indole-5-carboxamide derivatives (19, 32-34, and 42) General procedure: To a solution of 1-alkyl-1H-indole-5-carboxylic acids 18a or 41 (1.0mmol) in dichloromethane, different aromatic or aliphatic amines (1.2mmol), PyBop (1.2mmol) and DIPEA (2.4mmol) were successively added. Stirring was continued at room temperature for 12h. Afterward, the reaction mixture was diluted with dichloromethane (20mL), and the resulting solution was washed successively with 10% citric acid (2×25mL), 10% NaHCO3 (2×25mL), and water (2×25mL), dried over Na2SO4 and evaporated to dryness. Flash chromatography of the residues, using a mixture of ethyl acetate/n-hexane as eluent systems, yielded, in each case, the corresponding 5-carboxamide indole derivatives in 56-64% of yield.
  • 52
  • [ 110-89-4 ]
  • [ 186129-25-9 ]
  • (1-methyl-1H-indol-5-yl)(piperidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; 5.3 General method for coupling reactions. Synthesis of 1-alkyl-1H-indole-5-carboxamide derivatives (19, 32-34, and 42) General procedure: To a solution of 1-alkyl-1H-indole-5-carboxylic acids 18a or 41 (1.0mmol) in dichloromethane, different aromatic or aliphatic amines (1.2mmol), PyBop (1.2mmol) and DIPEA (2.4mmol) were successively added. Stirring was continued at room temperature for 12h. Afterward, the reaction mixture was diluted with dichloromethane (20mL), and the resulting solution was washed successively with 10% citric acid (2×25mL), 10% NaHCO3 (2×25mL), and water (2×25mL), dried over Na2SO4 and evaporated to dryness. Flash chromatography of the residues, using a mixture of ethyl acetate/n-hexane as eluent systems, yielded, in each case, the corresponding 5-carboxamide indole derivatives in 56-64% of yield.
  • 53
  • [ 75-04-7 ]
  • [ 186129-25-9 ]
  • N-ethyl-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; 5.3 General method for coupling reactions. Synthesis of 1-alkyl-1H-indole-5-carboxamide derivatives (19, 32-34, and 42) General procedure: To a solution of 1-alkyl-1H-indole-5-carboxylic acids 18a or 41 (1.0mmol) in dichloromethane, different aromatic or aliphatic amines (1.2mmol), PyBop (1.2mmol) and DIPEA (2.4mmol) were successively added. Stirring was continued at room temperature for 12h. Afterward, the reaction mixture was diluted with dichloromethane (20mL), and the resulting solution was washed successively with 10% citric acid (2×25mL), 10% NaHCO3 (2×25mL), and water (2×25mL), dried over Na2SO4 and evaporated to dryness. Flash chromatography of the residues, using a mixture of ethyl acetate/n-hexane as eluent systems, yielded, in each case, the corresponding 5-carboxamide indole derivatives in 56-64% of yield.
  • 54
  • [ 186129-25-9 ]
  • 3-(((2-([1,1'-biphenyl]-4-yl)ethyl)amino)methyl)-N-(4-fluorophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 55
  • [ 186129-25-9 ]
  • N-(4-fluorophenyl)-1-methyl-3-(((4-phenoxyphenethyl)amino)methyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 56
  • [ 186129-25-9 ]
  • 3-((([1,1'-biphenyl]-4-ylmethyl)amino)methyl)-N-(4-fluorophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 57
  • [ 186129-25-9 ]
  • N-(4-fluorophenyl)-1-methyl-3-((phenethylamino)methyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 58
  • [ 186129-25-9 ]
  • N-(4-fluorophenyl)-1-methyl-3-(((3,4,5-trimethoxybenzyl)amino)methyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 59
  • [ 186129-25-9 ]
  • 3-(((2-([1,1'-biphenyl]-4-yl)ethyl)amino)methyl)-1-methyl-N-(p-tolyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 60
  • [ 186129-25-9 ]
  • (3-(((2-([1,1'-biphenyl]-4-yl)ethyl)amino)methyl)-1-methyl-1H-indol-5-yl)(piperidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 61
  • [ 186129-25-9 ]
  • 3-(((2-([1,1'-biphenyl]-4-yl)ethyl)amino)methyl)-N-ethyl-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 62
  • [ 186129-25-9 ]
  • 3-(((2-([1,1'-biphenyl]-4-yl)ethyl)(methyl)amino)methyl)-N-(4-fluorophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: methanol; water / 1.5 h / 20 °C / Inert atmosphere; Molecular sieve 3.2: 3 h / 20 °C / Inert atmosphere; Molecular sieve
  • 63
  • [ 186129-25-9 ]
  • N-(4-fluorophenyl)-1-methyl-3-((methyl(4-phenoxyphenethyl)amino)methyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: methanol; water / 1.5 h / 20 °C / Inert atmosphere; Molecular sieve 3.2: 3 h / 20 °C / Inert atmosphere; Molecular sieve
  • 64
  • [ 186129-25-9 ]
  • 3-((([1,1'-biphenyl]-4-ylmethyl)(methyl)amino)methyl)-N-(4-fluorophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: methanol; water / 1.5 h / 20 °C / Inert atmosphere; Molecular sieve 3.2: 3 h / 20 °C / Inert atmosphere; Molecular sieve
  • 65
  • [ 186129-25-9 ]
  • N-(4-fluorophenyl)-1-methyl-3-((methyl(phenethyl)amino)methyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: methanol; water / 1.5 h / 20 °C / Inert atmosphere; Molecular sieve 3.2: 3 h / 20 °C / Inert atmosphere; Molecular sieve
  • 66
  • [ 186129-25-9 ]
  • N-(4-fluorophenyl)-1-methyl-3-((methyl(3,4,5-trimethoxybenzyl)amino)methyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: methanol; water / 1.5 h / 20 °C / Inert atmosphere; Molecular sieve 3.2: 3 h / 20 °C / Inert atmosphere; Molecular sieve
  • 67
  • [ 186129-25-9 ]
  • 3-(((2-([1,1'-biphenyl]-4-yl)ethyl)(methyl)amino)methyl)-1-methyl-N-(p-tolyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: methanol; water / 1.5 h / 20 °C / Inert atmosphere; Molecular sieve 3.2: 3 h / 20 °C / Inert atmosphere; Molecular sieve
  • 68
  • [ 186129-25-9 ]
  • (3-(((2-([1,1'-biphenyl]-4-yl)ethyl)(methyl)amino)methyl)-1-methyl-1H-indol-5-yl)(piperidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: methanol; water / 1.5 h / 20 °C / Inert atmosphere; Molecular sieve 3.2: 3 h / 20 °C / Inert atmosphere; Molecular sieve
  • 69
  • [ 186129-25-9 ]
  • 3-(((2-([1,1'-biphenyl]-4-yl)ethyl)(methyl)amino)methyl)-N-ethyl-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: methanol; water / 1.5 h / 20 °C / Inert atmosphere; Molecular sieve 3.2: 3 h / 20 °C / Inert atmosphere; Molecular sieve
  • 70
  • [ 186129-25-9 ]
  • 3-((N-(2-([1,1'-biphenyl]-4-yl)ethyl)acetamido)methyl)-N-(4-fluorophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: triethylamine / dichloromethane / 1 h / 20 °C
  • 71
  • [ 186129-25-9 ]
  • 3-((N-(2-([1,1'-biphenyl]-4-yl)ethyl)acetamido)methyl)-1-methyl-N-(p-tolyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C 3.1: triethylamine / dichloromethane / 1 h / 20 °C
  • 72
  • [ 186129-25-9 ]
  • N-(4-fluorophenyl)-1-methyl-3-((4-methylpiperazin-1-yl)methyl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 73
  • [ 186129-25-9 ]
  • 3-((4-([1,1'-biphenyl]-4-ylmethyl)piperazin-1-yl)methyl)-N-(4-fluorophenyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C 2.2: 20 °C
  • 74
  • [ 874-25-9 ]
  • [ 186129-25-9 ]
  • 2-oxo-2-(2-oxopyrrolidin-1-yl)ethyl 1-methyl-1H-indole-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
6.3 mg With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere;
  • 75
  • [ 60-27-5 ]
  • [ 186129-25-9 ]
  • 1-methyl-N-(1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20 - 30℃; Inert atmosphere; 2.1.4. Synthesis of 2-amino-1-methyl-1H-imidazole-4(5H)-one (creatinine)derivatives (4a-u) General procedure: Compounds (4a-u) synthesized from N-substituted-4-indole carboxylic acids (3a-o) and derivatives (4p-u) from heterocyclic carboxylic acids using standard amidation reaction. To a 100 ml single neck RB flask, (N-substituted-4-indole carboxylic acids (3a-u)) (1 eq/1mol), creatinine (1.5 eq/1.5 mol), HATU (1 eq/1 mol) and DMF(8-12 V) were added under nitrogen atmosphere and stirred for 5mins at 20-30 °C. Upon a clear solution formed, DIPEA (2 eq or 2 mol) was added and the reaction mass stirred again for 12-16 h at 20-30 °C. After 12-16 h, TLC/LCMS confirmed the completion of the reaction. Ice-cold water (20 volumes) was added slowly to the reaction mixture under stirring condition. The product was extracted with dichloromethane(2×10 volumes). The combined dichloromethane extract washed with(10 volumes) water and the organic layer separated then dried over anhydrous sodium sulfate. Further, the volatiles was distilled off under reduced pressure to get the crude product. The crude material further purified using column chromatography with silica as the stationary phase and MDC: MeOH as the mobile phase to get pure products (4a-u) with 60-88% yield.
  • 76
  • [ 1670-81-1 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: thionyl chloride / 2 h / Reflux 2.1: tetrabutylammonium salt / dichloromethane / 0.17 h / 0 - 5 °C / Alkaline conditions 2.2: 20 - 30 °C 3.1: lithium hydroxide / tetrahydrofuran; methanol; water / 20 - 30 °C
  • 77
  • [ 762-04-9 ]
  • [ 186129-25-9 ]
  • 3-((diethoxyphosphoryl)thio)-1-methyl-1H-indole-5-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% Stage #1: phosphonic acid diethyl ester; 1-methyl-1H-indole-5-carboxylic acid With sulfur; triethylamine; sodium iodide In ethanol at 60℃; for 0.166667h; Stage #2: With tert.-butylhydroperoxide; trifluoroacetic acid In ethanol; water at 60℃; for 8h;
  • 78
  • [ 10075-52-2 ]
  • [ 6482-39-9 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
50% Stage #1: 5-bromo-1-methyl-H-indole With iodine; magnesium In tetrahydrofuran at 60℃; for 16.25h; Inert atmosphere; Stage #2: sodium methyl carbonate In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;
  • 79
  • [ 186129-25-9 ]
  • [ 603-76-9 ]
YieldReaction ConditionsOperation in experiment
50% With triethylsilane; palladium diacetate; 2,2-dimethylpropanoic anhydride; 1,4-di(diphenylphosphino)-butane In toluene at 160℃; for 15h; chemoselective reaction;
  • 80
  • [ 186129-25-9 ]
  • [ 167627-05-6 ]
YieldReaction ConditionsOperation in experiment
87% With tert.-butylhydroperoxide; ferrous ammonium sulphate; diethoxymethylane In 2,2,2-trifluoroethanol at 50℃; for 10h; 18 Synthesis of Compound 18: In the air, 25 mg of reaction flask was added with ammonium ferrous sulfate (0.05 mmol).1r (0.5 mmol), methyldiethoxysilane (2.0 mmol),tert-Butyl Hydroperoxide (2 mmol) and trifluoroethanol (2.0 mL).After mixing uniformly at room temperature, the reaction mixture was reacted at 50 ° C for 10 h.At the end of the reaction, direct chromatography gave a yield of 87%.
  • 81
  • [ 762-04-9 ]
  • [ 186129-25-9 ]
  • diethyl (1-methyl-1H-indol-5-yl)phosphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With palladium diacetate; 2,2-dimethylpropanoic anhydride; triethylamine; 1,4-di(diphenylphosphino)-butane In 1,4-dioxane at 160℃; for 15h; Inert atmosphere; Schlenk technique;
  • 82
  • 4-[4-[[8-amino-3,4-dihydroquinoline-1(2H)]methyl]phenoxy]piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 186129-25-9 ]
  • C36H42N4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-methyl-1H-indole-5-carboxylic acid With HATU In N,N-dimethyl-formamide at 25℃; for 1h; Stage #2: 4-[4-[[8-amino-3,4-dihydroquinoline-1(2H)]methyl]phenoxy]piperidine-1-carboxylic acid tert-butyl ester With N-ethyl-N,N-diisopropylamine at 25℃; Tert-butyl 4-(4-((8-(4-methyl-4H-thieno[3,2-b]pyrrole-5-carboxamido)-3,4-dihydroquino- lin-1(2H)-yl)methyl)phenoxy)piperidine-1-carboxylate(M10f) General procedure: 4-Methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.18 g, 1.00 mmol) was added to a solution of HATU (0.38 g, 1.00 mmol) in 2 mL anhydrous DMF. The mixture was stirred at room temperature for one hour, and then intermediate M9f (0.39 g, 0.90 mmol) and N,N-diisopropylethylamine (0.13 g, 1.00 mmol) were added. The solution was stirred at room temperature until complete as indicated by TLC, poured into 20 mL water and extracted with ethyl acetate. The combined ethyl acetate was washed with water and brine, dried over anhydrous sodium sulfate, and condensed. Chromatography was performed on a silica gel (petroleum ether: ethyl acetate = 5: 1) to obtain M10f (0.36 g, 67.66 %) as a white solid.
  • 83
  • [ 620-08-6 ]
  • [ 186129-25-9 ]
  • (4-methoxypyridin-1-ium-1-yl)(1-methyl-1H-indole-5-carbonyl)amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% Stage #1: 4-methoxypyridine With mesitylenesulfonylhydroxylamine In dichloromethane for 2h; Stage #2: 1-methyl-1H-indole-5-carboxylic acid With oxalyl dichloride; triethylamine; N,N-dimethyl-formamide In dichloromethane at 20℃; for 24h;
  • 84
  • [ 3978-81-2 ]
  • [ 186129-25-9 ]
  • (4-(tert-butyl)pyridin-1-ium-1-yl)(1-methyl-1H-indole-5-carbonyl)amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: 4-tert-butylpyridine With mesitylenesulfonylhydroxylamine In dichloromethane for 2h; Stage #2: 1-methyl-1H-indole-5-carboxylic acid With chloroformic acid ethyl ester; potassium carbonate; triethylamine In dichloromethane for 24h;
  • 85
  • [ 186129-25-9 ]
  • 1-methyl-7,8-diphenyl-1,6-dihydro-5H-pyrrolo[2,3-g]isoquinolin-5-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: mesitylenesulfonylhydroxylamine / dichloromethane / 2 h 1.2: 24 h / 20 °C 2.1: [(1,2,3,4,5-pentamethylcyclopentadienyl)*Co(CH3CN)3](SbF6)2; Trimethylacetic acid / 48 h / 110 °C / Sealed tube; Inert atmosphere
Multi-step reaction with 2 steps 1.1: mesitylenesulfonylhydroxylamine / dichloromethane / 2 h 1.2: 24 h 2.1: [(1,2,3,4,5-pentamethylcyclopentadienyl)*Co(CH3CN)3](SbF6)2; Trimethylacetic acid / 48 h / 110 °C / Sealed tube; Inert atmosphere
  • 86
  • [ 10075-52-2 ]
  • [ 124-38-9 ]
  • [ 186129-25-9 ]
YieldReaction ConditionsOperation in experiment
61.6% Stage #1: 5-bromo-1-methyl-H-indole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran; hexane at -78 - 20℃; 4-Fluoro-2,6-dimethylbenzoic Acid (1); Typical Procedure General procedure: Under a positive pressure of N2, 2-bromo-5-fluoro-1,3-dimethylbenzene(3.040 g, 1.0 equiv, 14.97 mmol) was added to aflame-dried 100 mL round-bottomed flask and then dilutedwith anhyd THF (20 mL). The solution was cooled to -78 °C anda 1.6 M solution of n-BuLi (1.055 g, 1.1 equiv, 16.47 mmol) inhexanes (10.29 mL) was added dropwise. The resulting solutionwas then stirred at -78 °C for 1 h.Separately, under a constant stream of N2, anhyd THF (~50 mL)was added to a flame-dried, 250 mL Erlenmeyer flask andcooled to -78 °C. Freshly milled dry ice (~75 g) was slowly addedto the flask from a powder funnel. The flask was vigorouslyswirled, ensuring that the milled dry ice remained completelysubmerged in the solvent. The resulting slurry was filtered byvacuum filtration under a constant stream of N2. After completeremoval of the solvent, the resulting milled dry ice was quicklytransferred to the original round-bottomed reaction flask byusing a powder funnel (see the Supporting Information foradditional details).The resulting reaction mixture was removed from the coolingbath and stirred at r.t. until complete sublimation of the dry icewas observed. (Safety Note: Sublimation of dry ice produces alarge amount of gas. To prevent a dangerous buildup of pressure,the reaction flask was left open to the atmosphere afterdry ice addition.) The solution was then concentrated in vacuo,and the residue was dissolved in H2O (25 mL) and CH2Cl2 (25mL). The resulting bilayer mixture was transferred to a separatoryfunnel, and the organic layer was removed. The aqueouslayer was washed with CH2Cl2 (3 × 25 mL) and acidified to pH 2-3 with 1 M aq HCl. The resulting aqueous solution was thenextracted with CH2Cl2 (4 × 25 mL), and the organic layers werecollected, dried (MgSO4), filtered, and concentrated in vacuo togive a white solid; yield: 2.409 g (14.32 mmol, 95.68%, n = 4).
  • 87
  • [ 186129-25-9 ]
  • C20H16N2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% With oxygen; palladium diacetate; acetic acid In dimethyl sulfoxide at 95℃; for 24h; regioselective reaction;
  • 88
  • [ 36887-98-6 ]
  • [ 186129-25-9 ]
  • C19H19N3O [ No CAS ]
  • 89
  • N-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)cyclopropanesulfonamide hydrochloride [ No CAS ]
  • [ 186129-25-9 ]
  • N-(4-(cyclopropanesulfonamido)-2-(trifluoromethyl)benzyl)-1-methyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 60℃; for 0.75h; Microwave irradiation;
  • 90
  • 6,7-difluoro-4-(1-(methylamino)ethyl)isoquinolin-1(2H)-one [ No CAS ]
  • [ 186129-25-9 ]
  • N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N,1-dimethyl-1H-indole-5-carboxamide [ No CAS ]
  • N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N,1-dimethyl-1H-indole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 3h; 4-Chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide (Compounds 131 & 132) Racemic 4-chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide was prepared according to General procedure III from 4-chlorobenzoic acid. The enantiomers were subsequently separated by chiral SFC, Column: Chiralpak IC (250 x 30 mm, 5 m), 70% CO2/Methanol, Flow rate 100 g/min. 4-Chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide - Enantiomer I (Compound 131), LCMS: m/z found 377.3 [M+H]+, RT = 1.83 min (Method C); 1H NMR (400 MHz, DMSO-d6): δ 11.67 (s, 1H), 8.14 (t, 1H), 7.61 (t, 1H), 7.49 (d, 2H), 7.34 (d, 2H), 7.27 (s, 1H), 6.01 (q, 1H), 2.46 (s, 3H), 1.53 (d, 3H); Chiral analytical SFC: RT = 2.38 min, Column: Chiralpak IC-3, (4.6 x 150 mm, 3 m), 70% CO2/Methanol, Flow = 3.0 g/min.
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 3h; 4-Chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide (Compounds 131 & 132) Racemic 4-chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide was prepared according to General procedure III from 4-chlorobenzoic acid. The enantiomers were subsequently separated by chiral SFC, Column: Chiralpak IC (250 x 30 mm, 5 m), 70% CO2/Methanol, Flow rate 100 g/min. 4-Chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide - Enantiomer I (Compound 131), LCMS: m/z found 377.3 [M+H]+, RT = 1.83 min (Method C); 1H NMR (400 MHz, DMSO-d6): δ 11.67 (s, 1H), 8.14 (t, 1H), 7.61 (t, 1H), 7.49 (d, 2H), 7.34 (d, 2H), 7.27 (s, 1H), 6.01 (q, 1H), 2.46 (s, 3H), 1.53 (d, 3H); Chiral analytical SFC: RT = 2.38 min, Column: Chiralpak IC-3, (4.6 x 150 mm, 3 m), 70% CO2/Methanol, Flow = 3.0 g/min.
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 3h; 4-Chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide (Compounds 131 & 132) Racemic 4-chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide was prepared according to General procedure III from 4-chlorobenzoic acid. The enantiomers were subsequently separated by chiral SFC, Column: Chiralpak IC (250 x 30 mm, 5 m), 70% CO2/Methanol, Flow rate 100 g/min. 4-Chloro-N-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-N-methylbenzamide - Enantiomer I (Compound 131), LCMS: m/z found 377.3 [M+H]+, RT = 1.83 min (Method C); 1H NMR (400 MHz, DMSO-d6): δ 11.67 (s, 1H), 8.14 (t, 1H), 7.61 (t, 1H), 7.49 (d, 2H), 7.34 (d, 2H), 7.27 (s, 1H), 6.01 (q, 1H), 2.46 (s, 3H), 1.53 (d, 3H); Chiral analytical SFC: RT = 2.38 min, Column: Chiralpak IC-3, (4.6 x 150 mm, 3 m), 70% CO2/Methanol, Flow = 3.0 g/min.
  • 91
  • [ 2973-15-1 ]
  • [ 130-15-4 ]
  • [ 186129-25-9 ]
  • C40H23N5O12 [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% With tris(pentafluorophenyl)borate In acetonitrile at 120℃; for 24h; Inert atmosphere; 39 Example 39 Synthesis of naphthoquinone polycyclic derivative 5u 47.4 mg of 1,4-naphthoquinone, 53 mg of N-methyl-5-carboxyindole, 65 mg of N-(2-nitro)-phenylmaleimide were sequentially added to the reaction flask,15.4 mg of tris(pentafluorophenyl)borane was added, 3 mL of acetonitrile was added, and the reaction was carried out at 120°C for 24 h. After cooling to room temperature, saturated brine was added, and then extracted with dichloromethane. The organic phases were combined and extracted with anhydrous magnesium sulfate. The red solid 5u was obtained by precipitation, and the yield was 49%.
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