1235865-76-5

Usage

Uses

Used in Pharmaceutical Industry:
Methyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoate is used as a pharmaceutical compound for its potential therapeutic effects. The presence of the piperazine moiety, a common structural feature in many drug molecules, suggests that Methyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoate may have medicinal properties.
Used in Medicinal Chemistry:
Methyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoate is utilized in medicinal chemistry for its unique structure, which may offer novel avenues for drug development and the design of new therapeutic agents.
Used as a Reference Compound in Chemical Analysis:
Due to its distinctive chemical composition, Methyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoate serves as a reference compound in chemical analysis, aiding in the identification and characterization of similar compounds in research and development processes.

Synthetic route

methyl (2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl))benzoate + C16H21ClO3S → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; Inert atmosphere;	88%

1-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazine (1228780-72-0) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester (1235865-75-4) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
With dipotassium hydrogenphosphate In dimethyl sulfoxide at 140℃; for 12h; Inert atmosphere;	76%
With dipotassium hydrogenphosphate In dimethyl sulfoxide at 140℃; Inert atmosphere;	51%
With dipotassium hydrogenphosphate In dimethyl sulfoxide at 135℃; for 24h;

C27H33ClN2O3 + 5-bromo-1H-pyrrolo[2,3-b]pyridine (183208-35-7) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
With copper(l) iodide; t-butyl malonate; caesium carbonate In dimethyl sulfoxide at 120℃; for 12h; Solvent; Reagent/catalyst; Inert atmosphere;	75%

5-bromo-1H-pyrrolo[2,3-b]pyridine (183208-35-7) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h 1.2: 24 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran / 0.03 h / -78 °C 2.2: 1 h / -78 - 20 °C 2.3: 1 h / 0 °C 3.1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 4.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h 1.2: 24 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran / 0.03 h / -78 °C 2.2: 1 h / 20 °C 2.3: 1 h / 0 °C 3.1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 4.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h 1.2: 24 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.03 h / -78 °C 2.2: 1 h / -78 - 20 °C 3.1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 4.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (858116-66-2) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 0.03 h / -78 °C 1.2: 1 h / -78 - 20 °C 1.3: 1 h / 0 °C 2.1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 3.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 0.03 h / -78 °C 1.2: 1 h / 20 °C 1.3: 1 h / 0 °C 2.1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 3.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.03 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 3.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 0.03 h / -78 °C 1.2: 1 h / -78 - 20 °C 1.3: 1 h / 0 °C 2.1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 3.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium; Trimethyl borate / tetrahydrofuran / 1 h / -78 - 20 °C 1.2: 1 h / 0 °C 2.1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 3.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

methyl 4,4-dimethyl-2-oxocyclohexancarboxylate (32767-46-7) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydride / dichloromethane / 0.5 h / 0 °C 1.2: 24 h / -78 - 20 °C 2.1: cesium fluoride / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; methanol / 24 h / 70 °C 3.1: lithium borohydride; methanol / diethyl ether / 24 h / 20 °C 4.1: triethylamine; methanesulfonyl chloride / dichloromethane / 0.02 h / 0 °C 4.2: 24 h / 20 °C 5.1: trifluoroacetic acid; triethylsilane / dichloromethane / 1 h 6.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydride / dichloromethane / 0.5 h / 0 °C 1.2: -78 - 20 °C 2.1: cesium fluoride / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; methanol / 24 h / 70 °C 3.1: lithium borohydride; methanol / diethyl ether / 24 h / 20 °C 4.1: triethylamine; methanesulfonyl chloride / dichloromethane / 0.02 h / 0 °C 4.2: 24 h / 20 °C 5.1: trifluoroacetic acid; triethylsilane / dichloromethane / 1 h 6.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydride / dichloromethane / 0.5 h / 0 °C 1.2: 24 h / -78 - 20 °C 2.1: tetrakis(triphenylphosphine) palladium(0); cesium fluoride / 1,2-dimethoxyethane; methanol / 24 h / 70 °C 3.1: lithium borohydride / methanol / 24 h / 20 °C 4.1: methanesulfonyl chloride; triethylamine / dichloromethane / 0.02 h / 0 °C 4.2: 24 h / 20 °C 5.1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 6.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate (1228780-46-8) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: cesium fluoride / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; methanol / 24 h / 70 °C 2.1: lithium borohydride; methanol / diethyl ether / 24 h / 20 °C 3.1: triethylamine; methanesulfonyl chloride / dichloromethane / 0.02 h / 0 °C 3.2: 24 h / 20 °C 4.1: trifluoroacetic acid; triethylsilane / dichloromethane / 1 h 5.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrakis(triphenylphosphine) palladium(0); cesium fluoride / 1,2-dimethoxyethane; methanol / 24 h / 70 °C 2.1: lithium borohydride / methanol / 24 h / 20 °C 3.1: methanesulfonyl chloride; triethylamine / dichloromethane / 0.02 h / 0 °C 3.2: 24 h / 20 °C 4.1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 5.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 5 steps 1.1: cesium fluoride; tetrakis(triphenylphosphine) palladium(0) / methanol; 1,2-dimethoxyethane / 24 h / 70 °C 2.1: lithium borohydride; methanol / diethyl ether / 24 h / 20 °C 3.1: methanesulfonyl chloride; triethylamine / dichloromethane / 0.02 h / 0 °C 3.2: 24 h / 20 °C 4.1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 5.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid methyl ester (1228780-49-1) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium borohydride; methanol / diethyl ether / 24 h / 20 °C 2.1: triethylamine; methanesulfonyl chloride / dichloromethane / 0.02 h / 0 °C 2.2: 24 h / 20 °C 3.1: trifluoroacetic acid; triethylsilane / dichloromethane / 1 h 4.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium borohydride / methanol / 24 h / 20 °C 2.1: methanesulfonyl chloride; triethylamine / dichloromethane / 0.02 h / 0 °C 2.2: 24 h / 20 °C 3.1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 4.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium borohydride; methanol / diethyl ether / 24 h / 20 °C 2.1: methanesulfonyl chloride; triethylamine / dichloromethane / 0.02 h / 0 °C 2.2: 24 h / 20 °C 3.1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 4.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (1228780-51-5) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine; methanesulfonyl chloride / dichloromethane / 0.02 h / 0 °C 1.2: 24 h / 20 °C 2.1: trifluoroacetic acid; triethylsilane / dichloromethane / 1 h 3.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 3 steps 1.1: methanesulfonyl chloride; triethylamine / dichloromethane / 0.02 h / 0 °C 1.2: 24 h / 20 °C 2.1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 3.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 3 steps 1.1: methanesulfonyl chloride; triethylamine / dichloromethane / 0.02 h / 0 °C 1.2: 24 h / 20 °C 2.1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 3.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

tert-butyl 4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine-1-carboxylate (1228780-71-9) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: trifluoroacetic acid; triethylsilane / dichloromethane / 1 h 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 2 steps 1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 2 steps 1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate; dichloromethane / 3 h / 0 - 20 °C 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 12 h / 140 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: trifluoroacetic acid; triethylsilane / dichloromethane / 1 h 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (685514-01-6) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 2 steps 1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme
Multi-step reaction with 2 steps 1: potassium phosphate / diethylene glycol dimethyl ether / 24 h / 115 °C 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

4-Chlorophenylboronic acid (1679-18-1) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: cesium fluoride; tetrakis(triphenylphosphine) palladium(0) / methanol; 1,2-dimethoxyethane / 24 h / 70 °C 2.1: lithium borohydride; methanol / diethyl ether / 24 h / 20 °C 3.1: methanesulfonyl chloride; triethylamine / dichloromethane / 0.02 h / 0 °C 3.2: 24 h / 20 °C 4.1: triethylsilane; trifluoroacetic acid / dichloromethane / 1 h 5.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 24 h / 135 °C View Scheme

2-fluoro-4-nitro-benzoic acid methyl ester (392-09-6) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon / methanol / 760.05 Torr 3: potassium carbonate / tert-butyl alcohol / 48 h 4: potassium carbonate / N,N-dimethyl-formamide / 50 °C / Inert atmosphere View Scheme

C15H11N3O5 → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen; palladium 10% on activated carbon / methanol / 760.05 Torr 2: potassium carbonate / tert-butyl alcohol / 48 h 3: potassium carbonate / N,N-dimethyl-formamide / 50 °C / Inert atmosphere View Scheme

C15H13N3O3 → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / tert-butyl alcohol / 48 h 2: potassium carbonate / N,N-dimethyl-formamide / 50 °C / Inert atmosphere View Scheme

5-hydroxypyrrolo[2,3-b]pyridine (98549-88-3) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon / methanol / 760.05 Torr 3: potassium carbonate / tert-butyl alcohol / 48 h 4: potassium carbonate / N,N-dimethyl-formamide / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: potassium phosphate heptahydrate / diethylene glycol dimethyl ether / 115 °C / Inert atmosphere 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 140 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: potassium phosphate / 1,4-dioxane / 47 h / 34 - 90 °C 2.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 0.08 h / 29 °C / Inert atmosphere 2.2: 24.08 h / 29 - 120 °C View Scheme
Multi-step reaction with 3 steps 1: potassium phosphate / diethylene glycol dimethyl ether / 110 °C 2: dimethyl sulfoxide / 2 h / 90 °C 3: triethylamine / tetrahydrofuran / 3 h / 67 °C View Scheme
Multi-step reaction with 2 steps 1: potassium phosphate / diethylene glycol dimethyl ether / 10 h / 115 °C / Inert atmosphere 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 12 h / 140 °C / Inert atmosphere View Scheme

methyl 2,4-difluorobenzoate (106614-28-2) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium phosphate heptahydrate / diethylene glycol dimethyl ether / 115 °C / Inert atmosphere 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 140 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: potassium phosphate / 1,4-dioxane / 47 h / 34 - 90 °C 2.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 0.08 h / 29 °C / Inert atmosphere 2.2: 24.08 h / 29 - 120 °C View Scheme
Multi-step reaction with 3 steps 1: potassium phosphate / diethylene glycol dimethyl ether / 110 °C 2: dimethyl sulfoxide / 2 h / 90 °C 3: triethylamine / tetrahydrofuran / 3 h / 67 °C View Scheme
Multi-step reaction with 2 steps 1: potassium phosphate / diethylene glycol dimethyl ether / 10 h / 115 °C / Inert atmosphere 2: dipotassium hydrogenphosphate / dimethyl sulfoxide / 12 h / 140 °C / Inert atmosphere View Scheme

3,3-dimethylcyclohexanone (2979-19-3) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran / Reflux; Inert atmosphere 1.2: 4 h / Reflux 2.1: sodium hydride / dichloromethane / 0.83 h / 0 °C 2.2: -78 - 20 °C 3.1: tetrakis(triphenylphosphine) palladium(0); potassium fluoride / methanol; 1,2-dimethoxyethane / 16 h / 65 °C / Inert atmosphere 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere 5.1: triethylamine; methanesulfonyl chloride / dichloromethane / 0.05 h / 0 °C 5.2: 24 h / 0 °C 6.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 140 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: trichlorophosphate / dichloromethane / 1 h / 0 - 20 °C 1.2: 0 - 50 °C 2.1: tetrabutylammomium bromide; potassium carbonate; palladium diacetate / tetrahydrofuran; water / 30 - 35 °C / Inert atmosphere 3.1: sodium tetrahydroborate; methanol / 2 h / 0 - 5 °C 4.1: phosphorus tribromide; pyridine / cyclohexane / 2 h / 2 - 5 °C 5.1: triethylamine / tetrahydrofuran / 3 h / 67 °C View Scheme
Multi-step reaction with 8 steps 1.1: sodium hydride / tetrahydrofuran / 4 h / Inert atmosphere; Reflux 2.1: sodium hydride / dichloromethane / 0.5 h / 0 °C 2.2: -25 - 20 °C 3.1: tetrakis(triphenylphosphine) palladium(0); potassium fluoride / dichloromethane; methanol / 6 h / 65 °C / Inert atmosphere 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 °C 5.1: 1H-imidazole; triphenylphosphine; iodine / acetonitrile; diethyl ether / 1 h / -5 °C 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 80 °C 7.1: hydrogenchloride / ethyl acetate; dichloromethane / 3 h / 0 - 20 °C 8.1: dipotassium hydrogenphosphate / dimethyl sulfoxide / 12 h / 140 °C / Inert atmosphere View Scheme

2,4-difluoro-benzoic acid (1583-58-0) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydroxide / dimethyl sulfoxide / 8 h / 130 °C 2: thionyl chloride / 5 h / 60 °C 3: dimethyl sulfoxide / 5 h / 20 °C 4: sodium tris(acetoxy)borohydride / dichloromethane / 5 h / 30 °C 5: caesium carbonate; copper(l) iodide; t-butyl malonate / dimethyl sulfoxide / 12 h / 120 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: sulfuric acid / 8 h / 60 °C 2: potassium phosphate / diethylene glycol dimethyl ether / 110 °C 3: dimethyl sulfoxide / 2 h / 90 °C 4: triethylamine / tetrahydrofuran / 3 h / 67 °C View Scheme

4-fluorosalicylic acid (345-29-9) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / 5 h / 60 °C 2: dimethyl sulfoxide / 5 h / 20 °C 3: sodium tris(acetoxy)borohydride / dichloromethane / 5 h / 30 °C 4: caesium carbonate; copper(l) iodide; t-butyl malonate / dimethyl sulfoxide / 12 h / 120 °C / Inert atmosphere View Scheme

methyl 4-fluoro-2-hydroxybenzoate (392-04-1) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: dimethyl sulfoxide / 5 h / 20 °C 2: sodium tris(acetoxy)borohydride / dichloromethane / 5 h / 30 °C 3: caesium carbonate; copper(l) iodide; t-butyl malonate / dimethyl sulfoxide / 12 h / 120 °C / Inert atmosphere View Scheme

4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbaldehyde (1228837-05-5) + methyl (2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl))benzoate → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Stage #1: 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbaldehyde; methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate In tetrahydrofuran at 32℃; for 0.166667h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 5℃; for 20h;	48.2 mg

5-methoxy-1H-pyrrolo[2,3-b]pyridine (183208-36-8) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: boron tribromide / dichloromethane / 4 h / 0 - 27 °C 2: potassium phosphate / diethylene glycol dimethyl ether / 110 °C 3: dimethyl sulfoxide / 2 h / 90 °C 4: triethylamine / tetrahydrofuran / 3 h / 67 °C View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester (1235865-75-4) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: dimethyl sulfoxide / 2 h / 90 °C 2: triethylamine / tetrahydrofuran / 3 h / 67 °C View Scheme

methyl (2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl))benzoate + 1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
With triethylamine In tetrahydrofuran at 67℃; for 3h;	127 g

2-chloro-4,4-dimethyl-2-oxocyclohexenecarbaldehyde (1228943-80-3) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrabutylammomium bromide; potassium carbonate; palladium diacetate / tetrahydrofuran; water / 30 - 35 °C / Inert atmosphere 2: sodium tetrahydroborate; methanol / 2 h / 0 - 5 °C 3: phosphorus tribromide; pyridine / cyclohexane / 2 h / 2 - 5 °C 4: triethylamine / tetrahydrofuran / 3 h / 67 °C View Scheme

4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbaldehyde (1228837-05-5) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; methanol / 2 h / 0 - 5 °C 2: phosphorus tribromide; pyridine / cyclohexane / 2 h / 2 - 5 °C 3: triethylamine / tetrahydrofuran / 3 h / 67 °C View Scheme

4-chlorophenylboronic acid pinacol ester (195062-61-4) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions

Yield

Multi-step reaction with 6 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium fluoride / dichloromethane; methanol / 6 h / 65 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 °C 3: 1H-imidazole; triphenylphosphine; iodine / acetonitrile; diethyl ether / 1 h / -5 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 80 °C 5: hydrogenchloride / ethyl acetate; dichloromethane / 3 h / 0 - 20 °C 6: dipotassium hydrogenphosphate / dimethyl sulfoxide / 12 h / 140 °C / Inert atmosphere View Scheme

4'-chloro-6-(iodomethyl)-3,3-dimethyl-2,3,4,5-tetrahydro-1,1'-biphenyl → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 80 °C 2: hydrogenchloride / ethyl acetate; dichloromethane / 3 h / 0 - 20 °C 3: dipotassium hydrogenphosphate / dimethyl sulfoxide / 12 h / 140 °C / Inert atmosphere View Scheme

1-Chloro-4-iodobenzene (637-87-6) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5)

Conditions

Yield

Multi-step reaction with 7 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / dimethyl sulfoxide / 10 h / 95 °C / Inert atmosphere 2: tetrakis(triphenylphosphine) palladium(0); potassium fluoride / dichloromethane; methanol / 6 h / 65 °C / Inert atmosphere 3: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 °C 4: 1H-imidazole; triphenylphosphine; iodine / acetonitrile; diethyl ether / 1 h / -5 °C 5: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 80 °C 6: hydrogenchloride / ethyl acetate; dichloromethane / 3 h / 0 - 20 °C 7: dipotassium hydrogenphosphate / dimethyl sulfoxide / 12 h / 140 °C / Inert atmosphere View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → [2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid] (1235865-77-6)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; methanol; water at 45℃;	96.9%
With water; sodium hydroxide In tetrahydrofuran; ethanol at 20℃;	93%
With water; sodium hydroxide In dimethyl sulfoxide at 20℃; for 3h; Solvent; Reagent/catalyst; Temperature;	92%

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (1257044-40-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / 1,4-dioxane / 24 h / 50 °C 1.2: Cooling 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 24 h View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / 1,4-dioxane / 24 h / 50 °C 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / 1,4-dioxane / 24 h / 50 °C 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 24 h View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / 1,4-dioxane / 24 h / 50 °C 1.2: Cooling 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → {5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[(4-{[(trans-4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl}methyl dihydrogen phosphate trifluoroacetate

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydroxide / 1,4-dioxane / 24 h / 50 °C 1.2: Cooling 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 1.5 h / 80 °C / microwave irradiation 4.1: dichloromethane / 1 h View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → C56H73ClN7O11PS

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / 1,4-dioxane / 24 h / 50 °C 1.2: Cooling 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 1.5 h / 80 °C / microwave irradiation View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide hydrochloride

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / 1,4-dioxane / 24 h / 50 °C 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 3: hydrogenchloride / acetonitrile; water View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide sulfate (1379647-80-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / 1,4-dioxane / 24 h / 50 °C 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 3: sulfuric acid / isopropyl alcohol / 70 °C View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2R)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / 1,4-dioxane / 24 h / 50 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane 2.2: 1.5 h View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-N-((3-nitro-4-(3-((tetrahydro-2H-pyran-4-yl)oxy)prop-1-yn-1-yl)phenyl)sulfonyl)benzamide

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / tetrahydrofuran; methanol; water / 45 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 3 h / 20 °C 3: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 60 °C View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)sulfonyl)benzamide

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / tetrahydrofuran; methanol; water / 45 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 16 h / 20 °C 3: trifluoroacetic acid / dichloromethane / 3 h / 20 °C 4: sodium tris(acetoxy)borohydride / methanol; dichloromethane / 0.25 h / 20 °C View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → C50H57ClN8O7S

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydroxide / tetrahydrofuran; methanol; water / 45 °C 2: trichlorophosphate / 5 h / 85 °C 3: triethylamine / tetrahydrofuran / 20 °C 4: trifluoroacetic acid / dichloromethane / 20 °C 5: sodium tris(acetoxy)borohydride; sodium acetate / methanol; dichloromethane / 20 °C View Scheme

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester (1235865-76-5) → 6-(4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / tetrahydrofuran; methanol; water / 45 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 16 h / 20 °C View Scheme

Upstream product

• 1228780-72-0 1-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazine 
• 1235865-75-4 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester 
• 183208-35-7 5-bromo-1H-pyrrolo[2,3-b]pyridine 
• 858116-66-2 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 
• 32767-46-7 methyl 4,4-dimethyl-2-oxocyclohexancarboxylate 
• 1228780-46-8 methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate 
• 1228780-49-1 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid methyl ester 
• 1228780-51-5 (4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol 
• 1228780-71-9 tert-butyl 4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine-1-carboxylate 
• 685514-01-6 1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridin-5-ol 
• 1679-18-1 4-Chlorophenylboronic acid 
• 1257044-57-7 methyl (2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl))benzoate 
• 392-09-6 2-fluoro-4-nitro-benzoic acid methyl ester 
• 98549-88-3 5-hydroxypyrrolo[2,3-b]pyridine 

Downstream Products

• 1257044-40-8 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 

Relevant academic research and scientific papers

Potential applications of BPFP1 in Bcl-2 protein quantification, carcinoma cell visualization, cell sorting and early cancer diagnosis

Overexpression of the Bcl-2 protein has emerged as a hallmark of carcinoma cells and can be employed as a biochemical biomarker of these cells. Therefore, some Bcl-2 protein fluorescence probes (BPFPs) were designed for Bcl-2 protein quantification and carcinoma cells labeling. The high Bcl-2 protein binding affinity (Ki a range of concentrations of Bcl-2 protein, BPFP1 exhibited the desired fluorescence properties and its fluorescence intensity is proportional to Bcl-2 protein concentration. Therefore, BPFP1 provides a convenient approach for Bcl-2 protein quantification and we could determine the concentration of Bcl-2 protein based on the BPFP1's fluorescence intensity. Subsequent studies revealed that BPFP1 can fluorescently label carcinoma cells by binding to overexpressed Bcl-2 protein in living cells, and can distinguish carcinoma cells (HL-60 cells and ACHN cells) from normal-tissue cells (HUVECs) according to the different Bcl-2 protein expression levels between carcinoma cells and normal tissue cells. In the present study, BPFP1 represents a new tool for Bcl-2 protein quantification, carcinoma cell visualization and cell sorting. Moreover, BPFP1 can be used in the future for early cancer diagnosis by detecting carcinoma cells in patient tissues.

A PROCESS FOR THE PREPARATION OF VENETOCLAX AND ITS POLYMORPHS THEREOF

The present invention relates to a process for the preparation of 4-(4-{[2-(4-chlorophenyl)-4,4dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b] pyridin-5-yloxy)benzamide) compound of formula-1 which is represented by the following structural formula: Formula-1.

PROCESS FOR THE PREPARATION OF 4-(4-{[2-(4-CHLOROPHENYL)-4,4-DIMETHYLCYCLOHEX-1-EN-1- YL]METHYL}PIPERAZIN-1-YL)-N-({3-NITRO-4-[(TETRAHYDRO-2H-PYRAN-4-YLMETHYL)AMINO] PHENYL}SULFONYL)-2-(1H-PYRROLO[2,3-B]PYRIDIN-5-YLOXY)BENZAMIDE)

The present invention relates to novel crystalline forms of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran -4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide compound of formula-1 represented by the following structural formula-1, which is referred to as Venetoclax Formula-1 The present invention also relates to an improved process for the preparation of Venetoclax compound of formula-1 which is free of Impurity-I, Impurity-II, Impurity-III and Impurity-IV.

Solid dispersions containing an apoptosis-inducing agent

A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.

SOLID STATE FORMS OF AN APOPTOSIS-INDUCING AGENT AND PROCESSES THEREOF

Various crystalline and amorphous solid state forms of an apoptosis-inducing agent and preparations thereof are disclosed. Also discloses the use of crystalline forms for the preparation of amorphous form of apoptosis-inducing agent. Further discloses a process for preparation of the apoptosis-inducing agent. (Formula I)

PROCESS FOR THE PREPARATION OF VENETOCLAX

The present disclosure provides novel synthetic process for the preparation of venetoclax. The disclosed processes involve the use of novel intermediates. Processes for the preparation of these intermediates are also disclosed as well as methods for the preparation of particularly useful salts thereof.

N-benzenesulfonyl benzamide compound for inhibiting Bcl-2 proteins as well as composition and application thereof

The invention relates to a compound capable of inhibiting the activity of Bcl-2 anti-apoptosis protein as well as a preparation and application thereof, in particular to an N-benzenesulfonyl benzamidecompound for inhibiting Bcl-2 proteins as shown in formula (I), or a medicine composition of a crystal form, a precursor, a pharmaceutically-acceptable salt, a three-dimensional isomer, a solvent composition or a hydrate of the N-benzenesulfonyl benzamide compound. The compound and the composition containing the compound have excellent rejection capability for Bcl-2 proteins, have better pharmacokinetics parameter characteristics, can increase the medicine concentration of the compound in animal bodies, and can improve the drug curative effect and safety. (The formula (I) is shown in the description).

SOLID FORMS OF VENETOCLAX AND PROCESSES FOR THE PREPARATION OF VENETOCLAX

Aspects of the present application relate to solid forms of Venetoclax and preparative processes thereof. Specific aspects relate to an amorphous form of Venetoclax, its solid dispersion and crystalline forms of Venetoclax or salts thereof. Further aspects of the present application relate to processes for the preparation of Venetoclax.

Sulfonamide derivative and application thereof in pharmacy

The invention relates to a sulfonamide derivative and a pharmaceutical composition containing the same, and an application of the sulfonamide derivative and the pharmaceutical composition of the sulfonamide derivative in drug preparation, specifically the application in drug preparation of a BCL-2 family protein antagonist and the application in treatment of cancers.

A Bcl - 2 inhibitor venetoclax and intermediate preparation method (by machine translation)

The invention relates to a process for preparing Bcl - 2 inhibitor venetoclax required intermediate preparation method, a synthetic route thereof are shown below, in particular comprises the following steps: to compound I 2, 4 - difluoro-benzoic acid as the raw material, and after hydroxy methyl esterification reaction to obtain compound II 4 - fluorosalicylic acid methyl ester, compound II with the piperazine coupling to make the compound III, compound III and IV by the reaction of the raw material compound V, the compound V with compound VI 5 - bromo - 7 - aza indole C - O prepared by coupling compound VII, is intermediate. Preparation method of this invention mild reaction conditions, the operation is simple, environmental protection and high-efficiency and low cost, easy to manufacture on a large scale. (by machine translation)