1256387-87-7

Basic information

• Product Name: ledipasvir interMediate
• Synonyms: Identification Name (1R,3S,4S)-3-[6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester;tert-butyl (1R,3S,4S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate;(1R,3S,4S)-2-tert-Butyl-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-benzo[d]imidazol-2-yl);(1R,3S,4S)-tert-butyl 3-(6-(4,4,5,5-tetraMethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]iMidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate;2-Azabicyclo[2.2.1]heptane-2-carboxylic acid, 3-[6-(4,4,5,5-tetraMethyl-1,3,2-dioxaborolan-2-yl)-1H-benziMidazol-2-yl]-, 1,1-diMethylethyl ester, (1R,3S,4S)-;(1R,3S,4S)-3-[6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester;(1R,3S,4S)-2-tert-butyl-3-(6-(4,4,5,5-tetraMethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[D]iMidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate;2-Azabicyclo[2.
• CAS NO: 1256387-87-7
• Molecular Formula: C₂₄H₃₄BN₃O₄
• Molecular Weight: 141.16774
• EINECS: 1592732-453-0
• Mol File: 1256387-87-7.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 613.5±35.0 °C(Predicted)
• Appearance: /
• Density: 1.21±0.1 g/cm3(Predicted)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• PKA: 12.16±0.10(Predicted)
• CAS DataBase Reference: ledipasvir interMediate(CAS DataBase Reference)
• NIST Chemistry Reference: ledipasvir interMediate(1256387-87-7)
• EPA Substance Registry System: ledipasvir interMediate(1256387-87-7)

Safety Data

• Hazardous Substances Data: 1256387-87-7(Hazardous Substances Data)

Usage

General Description

Ledipasvir intermediate is a chemical compound that is an important intermediate in the synthesis of ledipasvir, which is an antiviral medication used to treat chronic hepatitis C virus (HCV) infection. The intermediate is a crucial building block in the manufacturing process of ledipasvir and is essential for the production of the final drug. It is a complex organic compound that is chemically modified and transformed through various reactions to eventually form ledipasvir. The intermediate is produced through a series of chemical reactions and purification processes, and its quality and purity are crucial in ensuring the effectiveness and safety of the final medication. The chemical structure and properties of the ledipasvir intermediate are carefully controlled and monitored to meet the stringent regulatory requirements for pharmaceutical manufacturing.

Synthetic route

(1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-74-2) + bis(pinacol)diborane (73183-34-3) → (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7)

Conditions	Yield
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In 1,4-dioxane at 90℃;	94%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 95℃; for 3.5h; Inert atmosphere;	1.16 g
With bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; potassium carbonate In 1,2-dimethoxyethane Reflux; Inert atmosphere;

(1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-74-2) + benzene-1,4-diboronic acid bispinacol ester (99770-93-1) → (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 90℃; for 4h; Inert atmosphere;	85%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 90℃; for 4h; Inert atmosphere;	85%

(1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester → (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; 4-methyl-morpholine / N,N-dimethyl-formamide / 1 h / 20 °C 2.1: ethanol / 130 - 170 °C / Sealed tube 2.2: 20 °C 3.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C 2: ethanol / 130 - 170 °C / Sealed tube 3: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C View Scheme
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C 1.2: 48 h / 115 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 95 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 1 h / 20 °C 2: ethanol / 72 h / 130 - 170 °C / Sealed tube 3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere View Scheme

(1R,3S,4S)-2-tert-butoxycarbonyl-3-(2-amino-4-bromophenylaminocarbonyl)-2-azabicyclo[2.2.1]heptane (1256387-73-1) → (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ethanol / 130 - 170 °C / Sealed tube 1.2: 20 °C 2.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: ethanol / 130 - 170 °C / Sealed tube 2: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C View Scheme
Multi-step reaction with 2 steps 1: ethanol / 72 h / 130 - 170 °C / Sealed tube 2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere View Scheme

4-Bromo-benzene-1,2-diamine (1575-37-7) → (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; 4-methyl-morpholine / N,N-dimethyl-formamide / 1 h / 20 °C 2.1: ethanol / 130 - 170 °C / Sealed tube 2.2: 20 °C 3.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C 1.2: 48 h / 115 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 95 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 1 h / 20 °C 2: ethanol / 72 h / 130 - 170 °C / Sealed tube 3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere View Scheme

(1R,3S,4S)-methyl 2-((R)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate → (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7)

Conditions

Yield

Multi-step reaction with 6 steps 1: palladium on carbon; hydrogen / ethanol; methanol / 15 h / 30 - 35 °C / 5171.62 Torr 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 3.5 h / 8 - 20 °C 3: lithium hydroxide / methanol; tetrahydrofuran; water / 0.08 h 4: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C 5: ethanol / 130 - 170 °C / Sealed tube 6: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C View Scheme

(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester → (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7)

Conditions

Yield

Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 3.5 h / 8 - 20 °C 2: lithium hydroxide / methanol; tetrahydrofuran; water / 0.08 h 3: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C 4: ethanol / 130 - 170 °C / Sealed tube 5: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C View Scheme

(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (1181573-36-3) → (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7)

Conditions

Yield

Multi-step reaction with 4 steps 1: lithium hydroxide / methanol; tetrahydrofuran; water / 0.08 h 2: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C 3: ethanol / 130 - 170 °C / Sealed tube 4: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C View Scheme

di-tert-butyl dicarbonate (24424-99-5) + (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → C29H42BN3O6

Conditions	Yield
With dmap In dichloromethane at 20℃; for 15h;	96.3%

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) + benzyl chloroformate (501-53-1) → C32H40BN3O6

Conditions	Yield
With dmap In dichloromethane at 20℃; for 15h;	96%

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) + (6S)-6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]heptane-5-carboxylic acid 1,1-dimethylethyl ester → (1R,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Conditions	Yield
With palladium diacetate; sodium carbonate; triphenylphosphine In 1,2-dimethoxyethane at 93℃; for 4h; Inert atmosphere;	95%
With palladium diacetate; sodium hydrogencarbonate; triphenylphosphine In 1,2-dimethoxyethane; water at 93℃; for 4h; Inert atmosphere;	90%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 93℃; for 4h; Inert atmosphere;	301 mg
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; triphenylphosphine In 1,4-dioxane; water; N,N-dimethyl-formamide at 80 - 85℃; Solvent; Reagent/catalyst; Inert atmosphere;	30 g

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) + acetyl chloride (75-36-5) → C26H36BN3O5

Conditions	Yield
With dmap In dichloromethane at 20℃; for 15h;	93.7%

(1-{6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1256388-50-7) + (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → 3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1256393-27-7)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tert-Amyl alcohol; water at 90℃; for 16h; Inert atmosphere;	92%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 85 - 90℃; for 5h; Inert atmosphere;	878 mg
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 85 - 90℃; for 5h; Inert atmosphere;

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) + (6S)-6-[4-(7-chloro-9,9-difluoro-9H-fluoren-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-yl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester → (6S)-6-[4-(7-(2-[(1R,3S,4S)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.2.1]heptan-3-yl]-1H-benzo[d]imidazole-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

Conditions	Yield
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate In 1,2-dimethoxyethane at 110℃; for 6h; Reagent/catalyst; Solvent; Temperature; Suzuki Coupling; Inert atmosphere;	89.5%

tert-butyl (S)-2-(5 -(7-bromo-9 ,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1256388-03-0) + (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → (1R,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1Himidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1256388-06-3)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate In 1,2-dimethoxyethane; water at 90℃; for 3h; Inert atmosphere;	77%

tert-butyl (S)-2-(5 -(7-bromo-9 ,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1256388-03-0) + (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → methyl (S)-1-((S)-2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(acetoxyamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (1256388-07-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; 1,2-dimethoxyethane / 3 h / 90 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane / 4 h / 20 °C 2.2: 0.5 h / 0 °C View Scheme

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → C45H48F2N6O4*ClH

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate; palladium diacetate; triphenylphosphine / water; 1,2-dimethoxyethane / 4 h / 93 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 0.33 h / 20 °C View Scheme

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]-hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate (1256388-51-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate; palladium diacetate; triphenylphosphine / water; 1,2-dimethoxyethane / 4 h / 93 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane; dichloromethane / 0.33 h / 20 °C 3: 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 / 0.33 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium carbonate; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water; N,N-dimethyl-formamide / 80 - 85 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane; water / 70 - 75 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.33 h / 23 °C 3.2: 4 h / 0 - 5 °C View Scheme
Multi-step reaction with 5 steps 1.1: triphenylphosphine; potassium carbonate / toluene / 20 - 105 °C 2.1: ammonium hydroxide 3.1: hydrogenchloride / water; acetonitrile / 2 h / 60 - 65 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 1.5 h / 20 - 30 °C 4.2: 20 - 30 °C 4.3: 2 h / 20 - 25 °C 5.1: ammonium hydroxide / water / 10 - 20 °C / pH 9 - 9.5 View Scheme

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate

Conditions

Yield

Multi-step reaction with 3 steps 1: hydrogenchloride / dichloromethane; 1,4-dioxane / 8 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 12 h / 0 °C 3: bis-triphenylphosphine-palladium(II) chloride; potassium propionate; potassium phosphate / water; Isopropyl acetate / 75 °C / Inert atmosphere View Scheme

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → 2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole hydrochloride

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; dichloromethane at 0 - 20℃; for 8h;	8.0 g

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → methyl ((S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-yl)carbamate (1378387-87-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / dichloromethane; 1,4-dioxane / 8 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 12 h / 0 °C View Scheme

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) + C27H27BrFN3O2 → C47H53FN6O4

Conditions	Yield
With potassium carbonate In 1,2-dimethoxyethane at 25 - 35℃; Reflux; Inert atmosphere;	12.9 g

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → 6-(7-(2-((S)-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazole

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water; N,N-dimethyl-formamide / 80 - 85 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane; water / 70 - 75 °C View Scheme

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) + C29H29BrF2N2O6 → C47H51F2N5O8

Conditions	Yield
With potassium dihydrogenphosphate; tetrakis(triphenylphosphine) palladium(0) In Isopropyl acetate; water at 80℃; Inert atmosphere;

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) + methyl (1-(6-(4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate + oxalic acid (144-62-7) → (x)C4H6O4*C47H51F2N7O5

Conditions

Yield

Stage #1: (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester; methyl (1-(6-(4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate In 1,2-dimethoxyethane at 20 - 30℃; Inert atmosphere; Stage #2: With potassium carbonate In 1,2-dimethoxyethane; water at 20 - 85℃; Stage #3: oxalic acid In acetone Reagent/catalyst; Solvent;

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) + methyl (1-(6-(4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate → C47H51F2N7O5*(x)H3O4P

Conditions

Yield

Stage #1: (1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester; methyl (1-(6-(4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate With potassium carbonate; triphenylphosphine In toluene at 20 - 105℃; Stage #2: With phosphoric acid In acetone

35 g

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → 3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1256393-27-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: Pd-101 / 1,2-dimethoxyethane / 20 - 30 °C / Inert atmosphere 1.2: 20 - 85 °C 2.1: ammonium hydroxide / water; ethyl acetate View Scheme
Multi-step reaction with 2 steps 1: triphenylphosphine; potassium carbonate / toluene / 20 - 105 °C 2: ammonium hydroxide View Scheme

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → (x)C2HF3O2*C42H43F2N7O3

Conditions	Yield
Multi-step reaction with 3 steps 1.1: Pd-101 / 1,2-dimethoxyethane / 20 - 30 °C / Inert atmosphere 1.2: 20 - 85 °C 2.1: ammonium hydroxide / water; ethyl acetate 3.1: dichloromethane / 2 h / 60 - 65 °C View Scheme
Multi-step reaction with 3 steps 1: triphenylphosphine; potassium carbonate / toluene / 20 - 105 °C 2: ammonium hydroxide 3: dichloromethane / 2 h / 60 - 65 °C View Scheme

(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-87-7) → C49H54N8O7

Conditions	Yield
Multi-step reaction with 6 steps 1.1: triphenylphosphine; potassium carbonate / toluene / 20 - 105 °C 2.1: ammonium hydroxide 3.1: hydrogenchloride / water; acetonitrile / 2 h / 60 - 65 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 1.5 h / 20 - 30 °C 4.2: 20 - 30 °C 4.3: 2 h / 20 - 25 °C 5.1: ammonium hydroxide / water / 10 - 20 °C / pH 9 - 9.5 6.1: trifluoroacetic acid / 48 h / 65 - 70 °C View Scheme
Multi-step reaction with 6 steps 1.1: Pd-101 / 1,2-dimethoxyethane / 20 - 30 °C / Inert atmosphere 1.2: 20 - 85 °C 2.1: ammonium hydroxide / water; ethyl acetate 3.1: hydrogenchloride / water; acetonitrile / 2 h / 60 - 65 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 1.5 h / 20 - 30 °C 4.2: 20 - 30 °C 4.3: 2 h / 20 - 25 °C 5.1: ammonium hydroxide / water / 10 - 20 °C / pH 9 - 9.5 6.1: trifluoroacetic acid / 48 h / 65 - 70 °C View Scheme

Upstream product

• 1575-37-7 4-Bromo-benzene-1,2-diamine 
• 1256387-74-2 (1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester 
• 99770-93-1 benzene-1,4-diboronic acid bispinacol ester 
• 1256387-73-1 3-(2-amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 
• 134795-25-8 (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 
• 1181573-36-3 (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester 
• 220093-41-4 (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester 
• 73183-34-3 bis(pinacol)diborane 

Downstream Products

• 1256393-27-7 3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 
• 1256388-51-8 methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]-hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate 

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