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[ CAS No. 1256584-75-4 ] {[proInfo.proName]}

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Chemical Structure| 1256584-75-4
Chemical Structure| 1256584-75-4
Structure of 1256584-75-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1256584-75-4 ]

CAS No. :1256584-75-4 MDL No. :MFCD22571223
Formula : C25H27IN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :QJJFMODIDDQXRV-UHFFFAOYSA-N
M.W : 514.40 Pubchem ID :66835052
Synonyms :

Calculated chemistry of [ 1256584-75-4 ]

Physicochemical Properties

Num. heavy atoms : 30
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.36
Num. rotatable bonds : 6
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 130.19
TPSA : 65.88 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -4.55 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.34
Log Po/w (XLOGP3) : 6.88
Log Po/w (WLOGP) : 6.49
Log Po/w (MLOGP) : 4.53
Log Po/w (SILICOS-IT) : 7.62
Consensus Log Po/w : 5.97

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.17

Water Solubility

Log S (ESOL) : -7.34
Solubility : 0.0000236 mg/ml ; 0.000000046 mol/l
Class : Poorly soluble
Log S (Ali) : -8.07
Solubility : 0.00000434 mg/ml ; 0.0000000084 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -9.16
Solubility : 0.000000359 mg/ml ; 0.0000000007 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.54

Safety of [ 1256584-75-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1256584-75-4 ]

* 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 [ 1256584-75-4 ]

[ 1256584-75-4 ] Synthesis Path-Downstream   1~27

  • 1
  • [ 877399-74-1 ]
  • [ 1256584-75-4 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 110℃; for 1.5h; Inert atmosphere; Microwave irradiation; 24 Synthesis of 2-(2-(3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-ethylphenyl) propan-2-yl)-1H-indole-6-carbonitrile (25) General procedure: A mixture of 23 (350 mg, 0.68 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (422 mg, 1.36 mmol), Pd(PPh3)4 (158 mg, 0.136 mmol), and Na2CO3 (2 M in water, 1.5 mL) in dioxane (4.5 mL) was degassed with nitrogen for 5 min and then heated at 110 °C under microwave for 1.5 h. After the completion of the reaction, the mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated and purified by chromatograph (petroleum/acetoacetate) to afford a yellow solid (275 mg, 71% yield). The obtained solid was dissolved in toluene/TFA (5 mL/5 mL). The mixture was heated at 80 °C for 3 h under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was evaporated in vacuum, and basified with saturated sodium bicarbonate until pH > 7. After extraction with EtOAc, the combined mixture was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatograph (CHCl3/MeOH) to give the corresponding intermediate as a pale yellow solid (80 mg, 45%). The intermediate (80 mg, 0.22 mmol) was dissolved in 2 mL of pyridine. Ac2O (0.24 mL, 2.6 mmol) and DMAP (3 mg, 0.025 mmol) were added. The solution was stirred at room temperature overnight until the completion of the reaction. After removal of the solventunder vacuum, DCM (80 mL) was added and the solution was washed with diluted hydrochloric acid (1 N) followed by brine, dried over sodium sulfate, and then ltered. After evaporation of the solvent, the residue was puried by chromatograph (CHCl3/ MeOH) to yield the title product 25 as a white solid (81 mg, 91%yield) (29% overall yield in three steps)
  • 2
  • [ 1256584-75-4 ]
  • [ 1820882-00-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane; water / 1.5 h / 110 °C / Inert atmosphere; Microwave irradiation 2: trifluoroacetic acid / toluene / 3 h / 80 °C / Inert atmosphere 3: pyridine; dmap / 20 °C
  • 3
  • [ 1256584-75-4 ]
  • [ 1820881-99-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane; water / 1.5 h / 110 °C / Inert atmosphere; Microwave irradiation 2: trifluoroacetic acid / toluene / 3 h / 80 °C / Inert atmosphere 3: pyridine; dmap / 20 °C
  • 4
  • [ 1256584-75-4 ]
  • [ 1820882-18-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane; water / 1.5 h / 110 °C / Inert atmosphere; Microwave irradiation 2: trifluoroacetic acid / toluene / 3 h / 80 °C / Inert atmosphere
  • 5
  • [ 1256584-75-4 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane; water / 1.5 h / 110 °C / Inert atmosphere; Microwave irradiation 2: trifluoroacetic acid / toluene / 3 h / 80 °C / Inert atmosphere
  • 6
  • [ 1256584-75-4 ]
  • [ 53617-35-9 ]
  • [ 1256698-41-5 ]
YieldReaction ConditionsOperation in experiment
74.53% With allylchloro[1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidine]palladium(II); sodium hexamethyldisilazane In tetrahydrofuran at 20 - 45℃; for 1h; Inert atmosphere; 8 EXAMPLE-08: PREPARATION OF tert-BUTYL 6-CYANO-2-[l-[4-ETHYL-3- (MORPHOLINO-l-PIPERIDYL)PHENYL]-l-METHYL-ETHYL]-lH- INDOLE-3- CARBOXYLA TE . Compound obtained in example-07 (200 g; 0.38 moles) and 4-morpholin-4-yl piperidine (79.43 g; 0.46 moles) were dissolved in THF under N2 atmosphere at 20- 30°C. NaHMDS (2.0M) in THF (437 g; 1.02 moles) was added at 20-40°C followed by l,3-bis-(2,6-diisopropylphenyl)-imidazoyl-2-ylidene(allyl) palladium- ill) chloride (6.7 g; 0.01 moles) at 30-40°C. Heated the reaction mass to 40-45°C and stirred for ~lh. After completion of the reaction by HPLC, reaction mass was diluted with ethyl acetate and aqueous ammonium chloride solution. Separated the organic layer and extracted the aqueous layer with ethyl acetate. Combined organic layer was washed with brine solution, treated with activated carbon and concentrated under vacuum at < 45°C. Co-distilled with acetone under vacuum at < 45°C, resulting residues were dissolved in acetone and added Cone. HC1. The precipitated solid was filtered, washed with acetone and dried under vacuum at 65- 70°C to obtain the title compound as a light cream colored powder (171.9 g; 74.53% of theory). HPLC Purity: 99.25%.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane at 60℃; Inert atmosphere; 25 Synthesis of 8-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-9-ethyl-6,6-dimethyl-11-oxo- 6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (7c) To a solution of 6b (150 mg, 0.34 mmol), tert-butyl 2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (109 mg, 0.51 mmol), Pd2(dba)3 (16 mg, 0.017 mmol) and S-Phos (28 mg, 0.068 mmol) in dry 1,4-dioxane (8.5 mL) was added NaHMDS (2 M in THF, 0.6 mL) under a nitrogen atmosphere. The mixture was purged with nitrogen for 5 min, and then heated at 60 °C until the completion of the reaction. After cooled to room temperature, the mixture was diluted with DCM (20 mL) and filtered. The filtrate was concentrated in vacuum and purified by chromatograph (CHCl3/MeOH) to give the coupling intermediate as pale yellow solid (103 mg, 59% yield): Subsequent deprotection of the intermediate with TFA (100 equiv) in DCM at room temperature afforded compound 7c as a yellow solid (69 mg, 49% yield in two steps).
  • 7
  • [ 1256584-75-4 ]
  • [ 53617-35-9 ]
  • [ 1820882-01-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; sodium hexamethyldisilazane; tris-(dibenzylideneacetone)dipalladium(0) / 1,4-dioxane; tetrahydrofuran / 60 °C / Inert atmosphere 2: trifluoroacetic acid / toluene / 80 °C
  • 8
  • [ 1256584-75-4 ]
  • [ 286961-14-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
71% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 110℃; for 1.5h; Inert atmosphere; Microwave irradiation; 23 Synthesis of 2-(2-(3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-ethylphenyl) propan-2-yl)-1H-indole-6-carbonitrile (25) A mixture of 23 (350 mg, 0.68 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (422 mg, 1.36 mmol), Pd(PPh3)4 (158 mg, 0.136 mmol), and Na2CO3 (2 M in water, 1.5 mL) in dioxane (4.5 mL) was degassed with nitrogen for 5 min and then heated at 110 °C under microwave for 1.5 h. After the completion of the reaction, the mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated and purified by chromatograph (petroleum/acetoacetate) to afford a yellow solid (275 mg, 71% yield): 1H NMR (300 MHz, CDCl3) δ 9.12 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.41 (dd, J = 8.4, 1.2 Hz, 1H), 7.16-7.07 (m, 2H), 6.98-6.91 (m, 1H), 5.52-5.45 (m, 1H), 4.04-3.94 (m, 2H), 3.59 (t, J = 5.5 Hz, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.36-2.24 (m, 2H), 1.91 (s, 6H), 1.48 (s, 9H), 1.37 (s, 9H), 1.16 (t, J = 7.5 Hz, 3H). The obtained solid was dissolved in toluene/TFA (5 mL/5 mL). The mixture was heated at 80 °C for 3 h under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was evaporated in vacuum, and basified with saturated sodium bicarbonate until pH > 7. After extraction with EtOAc, the combined mixture was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatograph (CHCl3/MeOH) to give the corresponding intermediate as a pale yellow solid (80 mg, 45%): 1H NMR (300 MHz, CDCl3 + CD3OD) δ 7.60-7.48 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 7.10-6.99 (m, 2H), 6.94 (s, 1H), 6.42 (s, 1H), 5.53-5.43 (m, 1H), 3.40-3.30 (m, 2H), 2.96 (t, J = 5.6 Hz, 2H), 2.53 (q, J = 7.5 Hz, 2H), 2.21-2.10 (m, 2H), 1.70 (s, 6H), 1.11 (t, J = 7.5 Hz, 3H). The intermediate (80 mg, 0.22 mmol) was dissolved in 2 mL of pyridine. Ac2O (0.24 mL, 2.6 mmol) and DMAP (3 mg, 0.025 mmol) were added. The solution was stirred at room temperature overnight until the completion of the reaction. After removal of the solventunder vacuum, DCM (80 mL) was added and the solution was washed with diluted hydrochloric acid (1 N) followed by brine, dried over sodium sulfate, and then ltered. After evaporation of the solvent, the residue was puried by chromatograph (CHCl3/ MeOH) to yield the title product 25 as a white solid (81 mg, 91%yield) (29% overall yield in three steps): 1H NMR (300 MHz, CDCl3)d 8.51 (s, 1H), 7.60 (d, J 8.1Hz, 1H), 7.55 (s, 1H), 7.33e7.27 (m, 1H),7.18e7.05 (m, 2H), 6.97 (s, 1H), 6.51 (s, 1H), 5.60e5.43 (m, 1H),4.20e4.12 (m, 1H), 4.11e4.00 (m, 1H), 3.82-3.72 (m, 1H), 3.66-3.58 (m, 1H), 2.56 (q, J 7.5 Hz, 2H), 2.41-2.26 (m, 2H), 2.17-2.07 (m,3H), 1.76 (s, 6H), 1.17 (t, J 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3)d 169.6 and 169.4 (1C), 152.0, 144.4, 141.9, 139.6 and 139.5 (1C),138.8, 136.7, 134.9, 131.7, 128.7, 126.0 and 125.9 (1C), 125.5, 123.0 and 122.8 (1C), 121.3, 120.8, 115.2, 103.4, 99.7, 45.5 and 43.5 (1C),41.8 and 38.4 (1C), 39.7, 31.2 and 30.5 (1C), 29.7, 25.6, 22.0 and 21.6 (1C), 15.7. MS (EI) 411 (M). HRMS: calcd for C27H29N3O (M),411.2311; found 411.2313.
  • 9
  • [ 1256584-75-4 ]
  • [ 1256584-78-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: allylchloro[1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidine]palladium(II); sodium hexamethyldisilazane / tetrahydrofuran / 1 h / 20 - 45 °C / Inert atmosphere 2: chloro-trimethyl-silane / 2,2,2-trifluoroethanol / 3 h / 5 - 30 °C / Inert atmosphere
  • 10
  • tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate [ No CAS ]
  • [ 1256580-46-7 ]
  • 11
  • [ 1256584-75-4 ]
  • [ 1256589-74-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: allylchloro[1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidine]palladium(II); sodium hexamethyldisilazane / tetrahydrofuran / 1 h / 20 - 45 °C / Inert atmosphere 2: chloro-trimethyl-silane / 2,2,2-trifluoroethanol / 3 h / 5 - 30 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; acetic anhydride / N,N-dimethyl-formamide / 1 h / 65 - 90 °C 4: acetic acid; pyrographite; hydrogenchloride / water; butanone; methanol / 1 h / 20 - 45 °C
Multi-step reaction with 4 steps 1.1: bis(η3-allyl-μ-chloropalladium(II)); dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; 1,3-dimethyl-2-imidazolidinone; sodium hexamethyldisilazane / tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 1.2: 1 h / 50 °C 1.3: 1 h / 35 °C 2.1: chloro-trimethyl-silane / 2,2,2-trifluoroethanol / 2 h / 30 °C / Inert atmosphere 3.1: diisopropyl-carbodiimide; N-ethyl-N,N-diisopropylamine / acetone / 4 h / 55 °C / Inert atmosphere 4.1: hydrogenchloride; acetic acid / water; butanone; ethanol / 1 h / 60 °C / Inert atmosphere
  • 12
  • [ 100-41-4 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: aluminum (III) chloride / 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran / -10 °C 2.1: zinc dibromide / 95 °C 3.1: sodium hydroxide; water / methanol / Reflux 4.1: N-iodo-succinimide; methanesulfonic acid / acetonitrile / 15 - 25 °C 5.1: magnesium chloride; triethylamine / tetrahydrofuran / 2 h / 10 - 30 °C / Inert atmosphere 5.2: 7 h / 10 - 65 °C / Inert atmosphere 6.1: sodium carbonate / N,N-dimethyl-formamide / 25 - 50 °C / Inert atmosphere 7.1: sodium dithionite / tetrahydrofuran; water / 4.5 h / 15 - 35 °C
  • 13
  • [ 698394-60-4 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: zinc dibromide / 95 °C 2.1: sodium hydroxide; water / methanol / Reflux 3.1: N-iodo-succinimide; methanesulfonic acid / acetonitrile / 15 - 25 °C 4.1: magnesium chloride; triethylamine / tetrahydrofuran / 2 h / 10 - 30 °C / Inert atmosphere 4.2: 7 h / 10 - 65 °C / Inert atmosphere 5.1: sodium carbonate / N,N-dimethyl-formamide / 25 - 50 °C / Inert atmosphere 6.1: sodium dithionite / tetrahydrofuran; water / 4.5 h / 15 - 35 °C
  • 14
  • [ 698394-59-1 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sodium hydroxide; water / methanol / Reflux 2.1: N-iodo-succinimide; methanesulfonic acid / acetonitrile / 15 - 25 °C 3.1: magnesium chloride; triethylamine / tetrahydrofuran / 2 h / 10 - 30 °C / Inert atmosphere 3.2: 7 h / 10 - 65 °C / Inert atmosphere 4.1: sodium carbonate / N,N-dimethyl-formamide / 25 - 50 °C / Inert atmosphere 5.1: sodium dithionite / tetrahydrofuran; water / 4.5 h / 15 - 35 °C
  • 15
  • [ 1247119-83-0 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-iodo-succinimide; methanesulfonic acid / acetonitrile / 15 - 25 °C 2.1: magnesium chloride; triethylamine / tetrahydrofuran / 2 h / 10 - 30 °C / Inert atmosphere 2.2: 7 h / 10 - 65 °C / Inert atmosphere 3.1: sodium carbonate / N,N-dimethyl-formamide / 25 - 50 °C / Inert atmosphere 4.1: sodium dithionite / tetrahydrofuran; water / 4.5 h / 15 - 35 °C
  • 16
  • [ 1256584-73-2 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: magnesium chloride; triethylamine / tetrahydrofuran / 2 h / 10 - 30 °C / Inert atmosphere 1.2: 7 h / 10 - 65 °C / Inert atmosphere 2.1: sodium carbonate / N,N-dimethyl-formamide / 25 - 50 °C / Inert atmosphere 3.1: sodium dithionite / tetrahydrofuran; water / 4.5 h / 15 - 35 °C
Multi-step reaction with 3 steps 1.1: magnesium chloride; triethylamine / toluene; isopropyl alcohol; 1,2-dimethoxyethane / 5 h / 25 - 30 °C 1.2: 10 h / 25 - 70 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 8 h / 25 - 50 °C 3.1: sodium dithionite / water; tetrahydrofuran / 5 h / 25 - 30 °C / Large scale
Multi-step reaction with 3 steps 1: acetyl chloride / 2 h / -3 - 40 °C / Inert atmosphere 2: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -6 - 15 °C 3: sodium hydroxide / tetrahydrofuran; water / 4 h / 5 - 15 °C
  • 17
  • [ 2287185-55-9 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
74.35% With sodium dithionite In tetrahydrofuran; water at 15 - 35℃; for 4.5h; 7 EXAMPLE-07: PREPARATION OF tert-BUTYL 6-CYANO-2-[l-(4- ETHYL-3-IODO-PHENYL)-l-METHYL-ETHYL]-lH-INDOLE-3- CARBOXYLATE . Compound obtained in example-06 (325 g; 0.57 moles) was dissolved in THF at 15-30°C and water was added to reaction solution. Sodium hydrosulfite (402.40 g; 2.31 moles) was added in small lots over a period of ~1.5h at 25-35°C and stirred for ~3h. After completion of the reaction by HPLC, layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic layer was treated with dil. aqueous hydrochloric acid, dil. sodium hydroxide and -15% w/v brine solution at 25-30°C. Organic layer was treated with activated carbon and concentrated under vacuum at < 50°C. Toluene added and co-distilled under vacuum at 50-60°C. Methanol was added followed by heated to 40-45°C and stirred for ~lh at 40-45°C. Cooled to 5-10°C, stirred for ~lh, filtered and washed with cold methanol. The wet product again suspended in methanol, heated to 40- 45°C and stirred for ~lh. Cooled to 5-10°C, stirred for ~lh, filtered and washed with cold methanol. Product was dried at 55-60°C under vacuum to obtain the title product as a white solid (221 g; 74.35% of theory). HPLC Purity: 98.96%.
13.8% With sodium dithionite In tetrahydrofuran; ethanol; water at 100℃; for 4h; 1.D; 2.D; 3.D D), Preparation of 6-cyano-2-(2- (4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylic acid tert-butyl ester The product obtained in the previous step4- (3-iodo-4-ethylphenyl) -2- (2-nitro-4-cyanophenyl) -4-methyl-3-oxopentanoic acid tert-butyl ester (15.7g, 0.03 mol) dissolved in 40mL of solution (THF: EtOH: H2O = 2: 2: 1),After stirring well, sodium dithionite (15.76 g, 0.09 mol) was slowly added, and the temperature was raised to 100 ° C and stirred for 4 h.After the reaction of the raw materials was detected by TLC, it was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.13.8 g of yellow solid was obtained6-cyano-2- (2- (4-ethyl-3-iodophenyl) propan-2-yl) -1H-indole-3-carboxylic acid tert-butyl ester,The reaction is as follows:
42.78 kg With sodium dithionite In tetrahydrofuran; water at 25 - 30℃; for 5h; Large scale; 7; 15 Example-15: Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)- lH-indole-3-carboxylate Tetrahydrofuran (330 lts) and water (385 lts) was added to tert-butyl 2-(4-cyano-2- nitrophenyl)-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate (55.0 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Sodium hydrosulfite (85.25 kgs) in five lots was added to the reaction mixture at 25-30°C and stirred for 5 hours at the same temperature. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer using ethyl acetate. Combined the organic layer and washed with aqueous sodium chloride solution. Aqueous hydrochloric acid solution was added to the organic layer at 25-30°C and stirred for 1 hour at the same temperature. Aqueous sodium hydroxide solution was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent from the organic layer under reduced pressure and then co-distilled with isopropanol. To the obtained compound, isopropanol (115.5 lts) was added at 25-30°C and stirred for 10 minutes at the same temperature. Water (49.5 lts) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with a mixture of isopropanol and water and dried to get the title compound. Yield: 42.78 kgs.
  • 18
  • [ 40052-13-9 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: magnesium chloride; triethylamine / toluene; isopropyl alcohol; 1,2-dimethoxyethane / 5 h / 25 - 30 °C 1.2: 10 h / 25 - 70 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 8 h / 25 - 50 °C 3.1: sodium dithionite / water; tetrahydrofuran / 5 h / 25 - 30 °C / Large scale
  • 19
  • [ 939-80-0 ]
  • [ 40052-13-9 ]
  • 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid [ No CAS ]
  • tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate [ No CAS ]
  • 20
  • [ 1256584-75-4 ]
  • [ 53617-35-9 ]
  • [ 1256584-77-6 ]
YieldReaction ConditionsOperation in experiment
35.2 kg Stage #1: tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate; 4-(piperidin-4-yl)morpholine With allylchloro[1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium(II); sodium hexamethyldisilazane In 1,2-dimethoxyethane at 25 - 50℃; for 5h; Large scale; Stage #2: With pyridine; hydrogenchloride In water; acetone at 10 - 15℃; for 0.333333h; Large scale; 8; 16 Example-16: Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin- l-yl)phenyl)propan-2-yl)-lH-indole-3-carboxylate hydrochloride Toluene (280 lts) was added to 4-(piperidin-4-yl)morpholine (26.40 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to H0-l l5°C and collect the water azeotropically and distilled off the solvent under reduced pressure. Dimethoxyethane (200 lts) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodo phenyl)propan-2- yl)-lH-indole-3-carboxylate (40.0 kgs) was added to the reaction mixture. Allylchloro[l,3- bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium (II) (1.60 kgs) and sodium hexamethyldisilazane (200 lts) was added to the reaction mixture at 25-30°C. Raised the temperature of the reaction mixture to 45-50°C and stirred for 5 hours at the same temperature. Isopropyl acetate (200 lts) was added to the reaction mixture at 25-30°C. Aqueous ammonium chloride solution was slowly added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Aqueous sodium chloride solution was added to the organic layer and stirred for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure. Dimethoxyethane (200 lts) and water (4.0 lts) was added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. N-acetyl cysteine (1.28 kgs) was added to the reaction mixture. Raised the temperature of the reaction mixture to 45-50°C and stirred for 1 hour at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with dimethoxyethane. Distilled off the solvent from the filtrate under reduced pressure. Acetone (400 lts) was added to the obtained compound. Pyridine (5.0 kgs) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to l0-l5°C. Hydrochloric acid (5.0 lts) was added to the reaction mixture at 10-15°C and stirred for 20 minutes at the same temperature. Ethanol (8.0 lts) and acetone (80 lts) was added to the reaction mixture at l0-l5°C and stirred for 10 minutes at the same temperature. Filtered the solid and pyridine was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with acetone and dried to get the title compound. Yield 35.20 kgs.
  • 21
  • [ 93420-33-8 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: acetic acid / 0.33 h / Cooling with ice 1.2: 24 h / 20 °C / Cooling with ice 2.1: sodium methylate / methanol / 6 h / 50 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 0.17 h 3.2: 12.5 h / 20 °C 4.1: sodium dithionite / tetrahydrofuran; ethanol; water / 4 h / 100 °C
  • 22
  • [ 2415924-34-2 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium methylate / methanol / 6 h / 50 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 0.17 h 2.2: 12.5 h / 20 °C 3.1: sodium dithionite / tetrahydrofuran; ethanol; water / 4 h / 100 °C
  • 23
  • [ 1256584-74-3 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.17 h 1.2: 12.5 h / 20 °C 2.1: sodium dithionite / tetrahydrofuran; ethanol; water / 4 h / 100 °C
  • 24
  • [ 1256584-75-4 ]
  • [ 1256584-80-1 ]
YieldReaction ConditionsOperation in experiment
10.7 g With Eaton's reagent at 20℃; for 2h; 1.E; 2.E; 3.E E) Preparation of 9-ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[B]carbazole-3-carbonitrile The obtained 6-cyano-2- (2- (4-ethyl-3-iodophenyl) propan-2-yl) -1H-indole-3-carboxylic acid tert-butyl ester (13.8 g, 0.025mol)Dissolved in 50mL of Eaton reagent and stirred at room temperature for 2h.After the reaction of the raw materials was detected by TLC, the reaction was quenched with 20 mL of water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.Obtained 10.7 g of a yellow solid9-ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile,Its reaction formula is as follows:
  • 25
  • [ 1009-35-4 ]
  • [ 1256584-74-3 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
95.96 g With sodium hydroxide In tetrahydrofuran; water at 5 - 15℃; 1.2 (2) (2) Synthesis of tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate (VIa) [Step 2] The THF solution (about 160 mL) of tert-butyl 4-(4-ethyl-3-iodo-phenyl)-4-methyl-3-oxo-pentanoate (IIIa) obtained in Step 1, and 4-fluoro-3-nitrobenzonitrile (IVa, 54.3 g, 327 mmol) were mixed, to which THF (742 mL) was further added, and the inside temperature of the reaction mixture was lowered to 5° C. An 8 mol/L aqueous solution of sodium hydroxide (210 mL, 1680 mmol) was added to the reaction mixture such that the inside temperature of the reaction mixture did not exceed 15° C., and the liquid was stirred at the same temperature for 4 hours. To the reaction mixture a 6 mol/L hydrochloric acid (293 mL, 1758 mmol) was added and reaction mixture the aqueous layer was discharged after raising the inside temperature of the reaction mixture to 25° C. Sodium hydrosulfite (253.9 g, 1260 mmol) was added to the obtained organic layer, and water (1000 mL) was dropped over 30 min. After completion of the dropwise addition, the reaction mixture was stirred at an inside temperature of 25° C. for 3 hours, and the aqueous layer was discharged after MTBE (314 mL) added to the reaction mixture. The obtained organic layer, to which a 1 mol/L hydrochloric acid (126 mL, 126 mmol) was added, was stirred at 25° C. for 1 hour, and a 1 mol/L aqueous solution of sodium hydroxide (293 mL, 293 mmol) was added thereto, then the aqueous layer was discharged after stirring. The resulting organic layer was washed with a 0.5 mol/L aqueous solution of sodium hydroxide (419 mL, 209.5 mmol). The washed organic layer was concentrated to about 160 mL, ethanol (314 mL) was added thereto, and it was concentrated again to 160 mL. The series of operations was repeated twice, and ethanol (1000 mL) was added to the obtained concentrated mixture, and the inside temperature of the reaction mixture was heated to 60° C. to dissolve the mixture. Water (115 mL) was added thereto over 15 min, and then the Compound VIa (524 mg) obtained by the production method described in WO 2010143664 was added as a seed crystal. Precipitation of crystals was confirmed, and the liquid was stirred at the same temperature for 1 hour. Water (230 mL) was dropped to the slurry at the same temperature over 2 hours, and then the inside temperature of the reaction mixture was lowered to 20° C. over 4 hours. The liquid was stirred for 1 hour after cooling, and a wet powder was collected by filtration. The wet powder was washed with a mixed solvent of ethanol and water (ethanol:water=10:3, total 520 mL). The wet powder was dried under a reduced pressure at the outside temperature of 50° C. to yield 95.96 g of tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate (VIa) was obtained in (yield 74.2%). HPLC purity: 99.52% Powder X-ray diffraction analysis: Compound (VIa) exhibited a pattern as shown in .
  • 26
  • [ 1256584-75-4 ]
  • [ 53617-35-9 ]
  • [ 1256584-77-6 ]
YieldReaction ConditionsOperation in experiment
91 % Stage #1: tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate; 4-(piperidin-4-yl)morpholine With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; 1,3-dimethyl-2-imidazolidinone; bis(η3-allyl-μ-chloropalladium(II)); sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: With ammonium chloride In Isopropyl acetate; water at 50℃; Stage #3: With pyridine hydrochloride In ethanol; acetone at 35℃; 1.3 (3) Production of tert-Butyl 6-cyano-2-[1-[4-ethyl-3-(4-morpholino-1-piperidyl)phenyl]-1-methyl-ethyl]-1H-indole-3-carboxylate hydrochloride (hydrochloride of VIIa) [Step 3] In a nitrogen atmosphere, π-allylpalladium chloride dimer (0.453 g, 2.48 mmol) and S-Phos (1.02 g, 2.48 mmol) were dissolved in THF (275 mL), and the inside of the reaction vessel was purged with nitrogen. To the obtained mixture, tert-butyl 6-cyano-2-[1-(4-ethyl-3-iodo-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylate (VIa, 65 g, 165 mmol) yielded in Step 2, 4-(4-piperidinyl)-morpholine (33.8 g, 198 mmol), and 1,3-dimethyl-2-imidazolidinone (149 mL) were added, and the inside of the reaction vessel was purged again with nitrogen. The mixture was cooled to 0° C., and NaHMDS (40% solution of THF, 280 mL, 545 mmol) was added such that the reaction temperature did not exceed 20° C. After completion of the addition, the reaction temperature was set at 25° C., and the mixture was stirred for 1 hour. Isopropyl acetate (340 mL), and an aqueous solution of ammonium chloride (15%, 255 g) were added thereto, the reaction temperature was heated to 50° C., and the liquid was stirred at the same temperature for 1 hour. The aqueous layer was discharged, and the resulting organic layer was concentrated at an outside temperature of 50° C. under a reduced pressure until the organic layer was concentrated to about 210 mL. Isopropyl acetate (340 mL) was added, then the liquid was concentrated to about 210 mL under a reduced pressure at the same temperature, and the residue was dissolved in acetone (255 mL). The solution was filtrated with a 1 μm-pore filter paper, and acetone (935 mL) was added to the obtained filtrate. After raising the temperature of the solution to 35° C., a mixed solution of an ethanol solution (21.3 mL) of pyridine hydrochloride (21 g, 182 mmol) and acetone (42.5 mL) was added dropwise over 1 hour to crystallize the objective substance. The resulting slurry was cooled to -4° C. over 1 hour, and filtrated to obtain a wet powder, which was then washed with acetone (425 mL). The wet powder was dried under a reduced pressure at an outside temperature of 40° C., to yield 97.1 g of tert-butyl 6-cyano-2-[1-[4-ethyl-3-(4-morpholino-1-piperidyl)phenyl]-1-methyl-ethyl]-1H-indole-3-carboxylate hydrochloride (hydrochloride of VIIa) (yield: 91%). (0182) HPLC purity: 99.13% (0183) Acetone content: 7.8% (0184) Powder X-ray diffraction analysis: Compound (VIIa) exhibited patterns as shown in FIG. 2, FIG. 3, and FIG. 4.
  • 27
  • [ 2126112-06-7 ]
  • [ 1256584-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -6 - 15 °C 2: sodium hydroxide / tetrahydrofuran; water / 4 h / 5 - 15 °C
Same Skeleton Products
Historical Records

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[ 1256584-75-4 ]

Iodides

Chemical Structure| 1256584-80-1

[ 1256584-80-1 ]

9-Ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

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Nitriles

Chemical Structure| 1256584-80-1

[ 1256584-80-1 ]

9-Ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Similarity: 0.80