1256387-74-2

Basic information

• Product Name: 2-Azabicyclo[2.2.1]heptane-2-carboxylic acid, 3-(6-broMo-1H-benziMidazol-2-yl)-, 1,1-diMethylethyl ester,(1R,3S,4S)-
• Synonyms: 2-Azabicyclo[2.2.1]heptane-2-carboxylic acid, 3-(6-broMo-1H-benziMidazol-2-yl)-, 1,1-diMethylethyl ester,(1R,3S,4S)-;(1R,3S,4S)-3-(6-Bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester;(1R,3S,4S)-tert-butyl 3-(6-broMo-1H-benzo[d]iMidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate;(1R,3S,4S)-tert-butyl 3-(6-broMo-1Hbenzo[d]iMidazol-2-yl)-2-azabicyclo[2,2,1] heptanes-2-carboxylate;Ledipasvir interMediates;(1R,3S,4S)-3-(6-Bromo-1Hbenzimidazol-2-yl)-2-azabicyclo[2,2,1]heptane--2-carboxylic acid-1,1-dimethylethyleste;Ledipasvir side chain 2;tert-butyl (1R,3S,4S)-3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate
• CAS NO: 1256387-74-2
• Molecular Formula: C₁₈H₂₂BrN₃O₂
• Molecular Weight: 392.29018
• EINECS: 1592732-453-0
• Mol File: 1256387-74-2.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 554.3±30.0 °C(Predicted)
• Appearance: /
• Density: 1.455±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• PKA: 10.68±0.10(Predicted)
• CAS DataBase Reference: 2-Azabicyclo[2.2.1]heptane-2-carboxylic acid, 3-(6-broMo-1H-benziMidazol-2-yl)-, 1,1-diMethylethyl ester,(1R,3S,4S)-(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Azabicyclo[2.2.1]heptane-2-carboxylic acid, 3-(6-broMo-1H-benziMidazol-2-yl)-, 1,1-diMethylethyl ester,(1R,3S,4S)-(1256387-74-2)
• EPA Substance Registry System: 2-Azabicyclo[2.2.1]heptane-2-carboxylic acid, 3-(6-broMo-1H-benziMidazol-2-yl)-, 1,1-diMethylethyl ester,(1R,3S,4S)-(1256387-74-2)

Safety Data

• Hazardous Substances Data: 1256387-74-2(Hazardous Substances Data)

Usage

General Description

2-Azabicyclo[2.2.1]heptane-2-carboxylic acid, 3-(6-bromo-1H-benzimidazol-2-yl)-, 1,1-dimethylethyl ester, (1R,3S,4S)- is a chemical compound that is commonly used in pharmaceutical research and development. It is a derivative of azabicyclic compounds and benzimidazoles, and its 1R,3S,4S stereochemistry is important for its biological activity. 2-Azabicyclo[2.2.1]heptane-2-carboxylic acid, 3-(6-broMo-1H-benziMidazol-2-yl)-, 1,1-diMethylethyl ester,(1R,3S,4S)- has potential applications in the treatment of central nervous system disorders and other medical conditions, and its specific properties and actions are of interest to scientists and researchers in the pharmaceutical industry.

Synthetic route

C18H24BrN3O3 → (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)

Conditions	Yield
With acetic acid In tert-butyl methyl ether at 70℃; Reagent/catalyst; Solvent; Temperature;	96.8%
With acetic acid In acetonitrile at 80℃; for 12h; Solvent;	87%

4-Bromo-benzene-1,2-diamine (1575-37-7) + (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester → (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)

Conditions	Yield
Stage #1: 4-Bromo-benzene-1,2-diamine; (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide at 10 - 20℃; for 20h; Cooling with ice; Stage #2: With acetic acid In tert-butyl methyl ether at 55℃; for 18h;	94%
Stage #1: 4-Bromo-benzene-1,2-diamine; (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: In ethanol at 115℃; for 48h;	1.59 g

(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-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-74-2)

Conditions	Yield
With ethanol at 130 - 170℃; for 72h; Sealed tube;	72%
In ethanol at 130 - 170℃; Sealed tube;	72%

di-tert-butyl dicarbonate (24424-99-5) + (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-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-74-2)

Conditions	Yield
Stage #1: 3-(2-amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester In ethanol at 130 - 170℃; Sealed tube; Stage #2: di-tert-butyl dicarbonate In dichloromethane at 20℃;	72%

C18H24BrN3O3 (1256387-73-1) → (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)

Conditions	Yield
With acetic acid at 50 - 60℃; for 3h;

(1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester → (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)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 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 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 / 3 h / 0 - 20 °C 2: iron(III) chloride hexahydrate; hydrazine hydrate; pyrographite / toluene; ethanol / 5 h / 60 - 65 °C 3: acetic acid / acetonitrile / 12 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1: pivaloyl chloride / -10 - -5 °C 2: pyridinium hydrobromide perbromide / N,N-dimethyl-formamide / 0 °C 3: acetic acid / tert-butyl methyl ether / 70 °C View Scheme
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 1 h / 20 °C 2: ethanol / 72 h / 130 - 170 °C / Sealed tube View Scheme

4-Bromo-benzene-1,2-diamine (1575-37-7) → (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)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 1 h / 20 °C 2: ethanol / 72 h / 130 - 170 °C / Sealed tube View Scheme

(1R,3S,4S)-methyl 2-((R)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate → (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)

Conditions

Yield

Multi-step reaction with 5 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 View Scheme

(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester → (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)

Conditions	Yield
Multi-step reaction with 4 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 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-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (1256387-74-2)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

5-bromo-2-nitroaniline (5228-61-5) → (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)

Conditions	Yield
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 / 3 h / 0 - 20 °C 2: iron(III) chloride hexahydrate; hydrazine hydrate; pyrographite / toluene; ethanol / 5 h / 60 - 65 °C 3: acetic acid / acetonitrile / 12 h / 80 °C View Scheme

C18H22BrN3O5 → (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)

Conditions	Yield
Multi-step reaction with 2 steps 1: iron(III) chloride hexahydrate; hydrazine hydrate; pyrographite / toluene; ethanol / 5 h / 60 - 65 °C 2: acetic acid / acetonitrile / 12 h / 80 °C View Scheme

1,2-diamino-benzene (95-54-5) → (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)

Conditions	Yield
Multi-step reaction with 3 steps 1: pivaloyl chloride / -10 - -5 °C 2: pyridinium hydrobromide perbromide / N,N-dimethyl-formamide / 0 °C 3: acetic acid / tert-butyl methyl ether / 70 °C View Scheme

(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) + 2-chloro-1-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)ethanone → (1R,3S,4S)-tert-butyl 3-(6-(7-(2-chloroacetyl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Conditions

Yield

Stage #1: 2-chloro-1-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)ethanone With potassium carbonate In Dimethyl ether; water at 20℃; for 0.166667h; Stage #2: (1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0) In Dimethyl ether; water at 90 - 95℃; Suzuki Coupling;

96%

(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)-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)-tert-butyl 3-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1256387-75-3)

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

(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) + (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 + oxalic acid (144-62-7) → C2H2O4*C45H48F2N6O4

Conditions

Yield

Stage #1: (1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester With bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; potassium propionate; bis(pinacol)diborane In Isopropyl acetate at 75℃; for 3.5h; Stage #2: (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 With potassium phosphate In Isopropyl acetate at 75℃; for 1h; Stage #3: oxalic acid Further stages;

81%

(S)-tert-butyl 2-(4-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-lH-imidazol-2-yl)pyrrolidine-1-carboxylate (1228552-26-8) + (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) → C40H46N6O4 (1273592-32-7)

Conditions	Yield
With sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane; water at 98℃; for 5h; Inert atmosphere;	62%

(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) + C30H38BN3O4 (1273592-38-3) → (1R,3S,4S)-tert-butyl 3-(6-(4'-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1Himidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1256387-76-4)

Conditions	Yield
With sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane; water at 98℃; for 2.5h; Inert atmosphere;	45%

(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) + trimethylsilylacetylene (1066-54-2) → C23H31N3O2Si (1273592-35-0)

Conditions	Yield
With triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) In acetonitrile at 85℃; 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) → C20H23N3O2 (1273592-36-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / acetonitrile / 85 °C / Inert atmosphere 2: potassium carbonate; methanol / 1.5 h / 20 °C View Scheme

(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) → C38H44N6O4 (1273592-22-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / acetonitrile / 85 °C / Inert atmosphere 2: potassium carbonate; methanol / 1.5 h / 20 °C 3: triethylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / acetonitrile / 15 h / 35 °C / Inert atmosphere View Scheme

(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) → 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: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere 2: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 5 h / 85 - 90 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere 2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,2-dimethoxyethane; water / 5 h / 85 - 90 °C / Inert atmosphere View Scheme

(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) → (1R,3S,4S)-tert-butyl 3-(6-(4'-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1Himidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1256387-76-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; 1,2-dimethoxyethane / 4 h / 90 °C / Inert atmosphere 2: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; 1,2-dimethoxyethane / 90 °C / Inert atmosphere View Scheme

(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) → (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
Multi-step reaction with 2 steps 1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C 2: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; 1,2-dimethoxyethane / 3 h / 90 °C / Inert atmosphere View Scheme

(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) → (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
Multi-step reaction with 2 steps 1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C 2: sodium hydrogencarbonate; palladium diacetate; triphenylphosphine / water; 1,2-dimethoxyethane / 4 h / 93 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 3.5 h / 95 °C / Inert atmosphere 2: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,2-dimethoxyethane; water / 4 h / 93 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; potassium acetate / 1,4-dioxane / 80 - 85 °C 2: sodium carbonate; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water; N,N-dimethyl-formamide / 80 - 85 °C / Inert atmosphere View Scheme

(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) → C45H48F2N6O4*ClH

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C 2: sodium hydrogencarbonate; palladium diacetate; triphenylphosphine / water; 1,2-dimethoxyethane / 4 h / 93 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane; dichloromethane / 0.33 h / 20 °C View Scheme

(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) → methyl (S)-1-((S)-2-(5-(4'-(2-((1R,3S,4S)-2-((S)-2-(acetoxyamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1Himidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (1256387-78-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; 1,2-dimethoxyethane / 4 h / 90 °C / Inert atmosphere 2.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; 1,2-dimethoxyethane / 90 °C / Inert atmosphere 3.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 2 h / 20 °C 3.2: 0.83 h / 0 °C View Scheme

(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) → 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 3 steps 1.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C 2.1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; 1,2-dimethoxyethane / 3 h / 90 °C / Inert atmosphere 3.1: hydrogenchloride / 1,4-dioxane / 4 h / 20 °C 3.2: 0.5 h / 0 °C View Scheme

(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) → 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 4 steps 1: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 1,4-dioxane / 90 °C 2: sodium hydrogencarbonate; palladium diacetate; triphenylphosphine / water; 1,2-dimethoxyethane / 4 h / 93 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane; dichloromethane / 0.33 h / 20 °C 4: 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: potassium propionate; bis(pinacol)diborane / Isopropyl acetate / 3 h / 75 °C / Inert atmosphere 1.2: 15 h / 75 °C / Inert atmosphere 2.1: hydrogenchloride / acetonitrile; water / 6 h / 65 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 0.5 h / 0 °C 3.2: 4 h / 25 °C View Scheme
Multi-step reaction with 5 steps 1: hydrogenchloride / acetonitrile / 3 h / 60 - 65 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / N,N-dimethyl-formamide; ethyl acetate / 16 h / 0 - 30 °C 3: potassium propionate / Isopropyl acetate / 69 - 72 °C / Inert atmosphere 4: potassium phosphate / Isopropyl acetate; water / 2 h / 65 - 72 °C 5: ammonium acetate / toluene; 2-methoxy-ethanol / 5 h / 100 - 102 °C View Scheme
Multi-step reaction with 4 steps 1.1: bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; potassium acetate / 1,4-dioxane / 80 - 85 °C 2.1: sodium carbonate; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water; N,N-dimethyl-formamide / 80 - 85 °C / Inert atmosphere 3.1: hydrogenchloride / 1,4-dioxane; water / 70 - 75 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.33 h / 23 °C 4.2: 4 h / 0 - 5 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium propionate; bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; Isopropyl acetate / 3 h / 70 °C / Inert atmosphere 2.1: aq. phosphate buffer / 0.5 h / 70 °C / Inert atmosphere 2.2: 0.5 h / 35 °C / Inert atmosphere 2.3: 9 h / 55 °C 3.1: hydrogenchloride / water; acetonitrile / 1.5 h / 60 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C / Autoclave 4.2: 3.5 h / 0 - 20 °C / Autoclave View Scheme

(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) + (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

Stage #1: (1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester With potassium propionate; bis(pinacol)diborane In Isopropyl acetate at 75℃; for 3h; Inert atmosphere; Stage #2: (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 With palladium diacetate; sodium hydrogencarbonate; triphenylphosphine In acetonitrile at 75℃; for 15h; Inert atmosphere;

50 g

Upstream product

• 95-54-5 1,2-diamino-benzene 
• 5228-61-5 5-bromo-2-nitroaniline 
• 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 
• 24424-99-5 di-tert-butyl dicarbonate 
• 1256387-73-1 3-(2-amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 
• 1575-37-7 4-Bromo-benzene-1,2-diamine 
• 134795-25-8 (1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 
• 1256387-73-1 C₁₈H₂₄BrN₃O₃ 

Downstream Products

• 1273592-22-5 C₃₈H₄₄N₆O₄ 
• 1256387-76-4 (1R,3S,4S)-tert-butyl 3-(6-(4'-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1Himidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate 
• 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 
• 1256387-87-7 (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 
• 1256387-78-6 methyl (S)-1-((S)-2-(5-(4'-(2-((1R,3S,4S)-2-((S)-2-(acetoxyamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1Himidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate 
• 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 
• 1502654-87-6 (1-{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-carbonyl}-2-methyl-propyl)carbamicacid methyl ester D-tartrate salt 
• 1256387-75-3 (1R,3S,4S)-tert-butyl 3-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate 

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