211915-84-3

Basic information

• Product Name: 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl ester
• Synonyms: 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl ester;Ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido;Dabigatran Intermediate 3;Ethyl 3-(2-((4-cyanophenylaMino)Methyl)-1-Methyl-N-(pyridin-2-yl)-1H-benzo[d]iMi;Ethyl 3-(2-((4-cyanophenylaMino)Methyl)-1-Methyl-N-(pyridin-2-yl)-;3-[[[2-[[(4-Cyanophenyl)aMino]Methyl]-1-Methyl-1H-benziMidazol-5-yl]carbonyl]pyridin-2-ylaMino]propi;Ethyl 3-[[[2-[[(4-Cyanophenyl)aMino]Methyl]-1-Methyl-1H-benziMidazol-5-yl]carbonyl]pyridin-2-ylaMino] propionate;Ethyl N-[(2-{[(4-cyanophenyl)aMino]Methyl}-1-Methyl-1H-benziMidazol-5-yl)carbonyl]-N-pyridin-2-yl-beta-alaninate
• CAS NO: 211915-84-3
• Molecular Formula: C₂₇H₂₆N₆O₃
• Molecular Weight: 482.53
• EINECS: 1592732-453-0
• Product Categories: Intermediate of Dabigatran;pyridine;nitrile;Dabigatran intermediate;benzimidazole
• Mol File: 211915-84-3.mol
• Article Data: 29

Chemical Properties

• Boiling Point: 756.382 °C at 760 mmHg
• Flash Point: 411.245 °C
• Appearance: /
• Density: 1.255 g/cm³
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: DMSO (Slightly, Sonicated), Methanol (Very Slightly, Sonicated)
• PKA: 4.21±0.10(Predicted)
• CAS DataBase Reference: 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl ester(211915-84-3)
• EPA Substance Registry System: 3-[[[2-[[(4-Cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]propionic acid ethyl ester(211915-84-3)

Safety Data

• Hazardous Substances Data: 211915-84-3(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Uses

Nonpeptide thrombin inhibitor intermediate.

Synthetic route

1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide p-toluenesulfonate → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
With ammonium hydroxide In dichloromethane; water pH=8 - 10;	95.5%

(4-cyanophenyl)glycine (42288-26-6) + ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine; ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate With 1,1'-carbonyldiimidazole In Isopropyl acetate at 20℃; for 4h; Stage #2: With acetic acid In Isopropyl acetate for 2h; Reflux;	95%
Stage #1: (4-cyanophenyl)glycine With 1,1'-carbonyldiimidazole In toluene at 50℃; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In toluene at 20 - 25℃; Temperature;	93.97%
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 3℃; for 1h; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In N,N-dimethyl-formamide at 20℃; for 6h; Temperature; Further stages;	91.1%

3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-pyridin-2-yl-amino)-ethyl propanoate (948551-71-1) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
With acetic acid at 110℃; for 2h; Large scale;	92%
With acetic acid In acetic acid butyl ester at 85 - 90℃;	90.8%
Stage #1: 3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-pyridin-2-yl-amino)-ethyl propanoate With acetic acid In dichloromethane at 80 - 85℃; for 10h; Large scale; Stage #2: With ammonia In dichloromethane pH=9; Reagent/catalyst; Solvent; Large scale;	83.3%
With acetic acid for 1h; Heating;
In toluene Reflux;	120 g

isopropyl 2‑(4‑cyanophenylamino)acetate + ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 10 - 35℃;	82%

ethyl 2-((4-cyanophenyl)amino)acetate + ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
In propionic acid at 130℃; for 12h; Solvent; Temperature;	81%

2-(4-cyanophenylamino)acetamide + C19H23N3O4 → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
With acetic acid; 1,1'-carbonyldiimidazole In ethyl acetate at 50℃; for 6h; Concentration;	47.7%

4-methylamino-3-nitro-benzoic acid chloride (82357-48-0) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: Et3N / tetrahydrofuran / 20 °C 2.1: 65 percent / H2 / 10percent Pd/C / methanol / 20 °C 3.1: CDI / tetrahydrofuran / 50 °C 3.2: tetrahydrofuran / 24 h / Heating 4.1: glacial acetic acid / 1 h / Heating View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran; dichloromethane / 2 h / 40 °C 2.1: palladium on activated charcoal; hydrogen / water; ethanol / 50 °C / Autoclave 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.67 h / Inert atmosphere; Reflux 3.2: 7 h / Inert atmosphere; Reflux 3.3: 3 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0 - 10 °C 1.2: 0 - 30 °C 2.1: hydrogen / ethyl acetate / 60 - 65 °C / 7500.75 Torr 3.1: pivaloyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 5 °C 3.2: 0.08 h / 0 - 5 °C 4.1: ammonium hydroxide / water; dichloromethane / pH 8 - 10 View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 12 h / 20 °C 2.1: palladium 10% on activated carbon / 20 h / 22801.5 Torr 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 0.75 h / 0 °C 3.2: 20 °C View Scheme

4-(methylamino)-3-nitrobenzoic acid (41263-74-5) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: SOCl2 / dimethylformamide / 0.5 h / Heating 2.1: Et3N / tetrahydrofuran / 20 °C 3.1: 65 percent / H2 / 10percent Pd/C / methanol / 20 °C 4.1: CDI / tetrahydrofuran / 50 °C 4.2: tetrahydrofuran / 24 h / Heating 5.1: glacial acetic acid / 1 h / Heating View Scheme
Multi-step reaction with 4 steps 1.1: thionyl chloride / tetrahydrofuran / 0.67 - 0.75 h / Reflux; Inert atmosphere 2.1: triethylamine / tetrahydrofuran; dichloromethane / 2 h / 40 °C 3.1: palladium on activated charcoal; hydrogen / water; ethanol / 50 °C / Autoclave 4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.67 h / Inert atmosphere; Reflux 4.2: 7 h / Inert atmosphere; Reflux 4.3: 3 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 1.25 h / 25 - 80 °C 1.2: 1 h 2.1: palladium on activated charcoal / ethyl acetate / 0.33 h / 25 - 55 °C / High pressure 3.1: 1,1'-carbonyldiimidazole / toluene / 2 h / 55 - 60 °C 3.2: 6 h / 60 - 100 °C View Scheme

ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: CDI / tetrahydrofuran / 50 °C 1.2: tetrahydrofuran / 24 h / Heating 2.1: glacial acetic acid / 1 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: pivaloyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 5 °C 1.2: 0.08 h / 0 - 5 °C 2.1: ammonium hydroxide / water; dichloromethane / pH 8 - 10 View Scheme
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C 1.2: 20 °C 2.1: acetic acid / acetic acid butyl ester / 85 - 90 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 6 h / 0 - 5 °C / Large scale 1.2: 24 h / 20 °C / Large scale 2.1: acetic acid / dichloromethane / 10 h / 80 - 85 °C / Large scale 2.2: pH 9 / Large scale View Scheme

ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (429659-01-8) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 65 percent / H2 / 10percent Pd/C / methanol / 20 °C 2.1: CDI / tetrahydrofuran / 50 °C 2.2: tetrahydrofuran / 24 h / Heating 3.1: glacial acetic acid / 1 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: palladium on activated charcoal / ethyl acetate / 0.33 h / 25 - 55 °C / High pressure 2.1: 1,1'-carbonyldiimidazole / toluene / 2 h / 55 - 60 °C 2.2: 6 h / 60 - 100 °C View Scheme
Multi-step reaction with 2 steps 1.1: palladium on activated charcoal / ethyl acetate / 25 - 55 °C 2.1: 1,1'-carbonyldiimidazole / toluene / 25 - 60 °C 2.2: 6 h / 60 - 100 °C View Scheme

4-Aminobenzonitrile (873-74-5) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium iodide; sodium hydrogencarbonate; tetrabutylammomium bromide / water / 24 h / 90 - 95 °C 1.2: 0.33 h / 20 - 30 °C / pH 7.5 1.3: 3 h / 20 - 30 °C / pH 2.5 2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 2 h / 50 - 55 °C 2.2: 50 h / 50 - 65 °C View Scheme
Multi-step reaction with 2 steps 1.1: water / 16 h / 100 °C 2.1: 1,1'-carbonyldiimidazole / toluene / 2 h / 55 - 60 °C 2.2: 6 h / 60 - 100 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium iodide; tetrabutylammomium bromide; sodium hydrogencarbonate / water / 24 h / 90 - 95 °C 2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 50 - 55 °C 2.2: 52 h / 50 - 65 °C 2.3: 5 h / 95 - 100 °C View Scheme

ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2-yl)amino]propanoate hydrochloride hemisulfate → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: palladium on activated charcoal; hydrogen / water; ethanol / 50 °C / Autoclave 2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.67 h / Inert atmosphere; Reflux 2.2: 7 h / Inert atmosphere; Reflux 2.3: 3 h / Reflux View Scheme

2-chloromethyl-1-methyl-1H-benzimidazole-5 ethyl acetate (103041-38-9) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0 - 10 °C 1.2: 0 - 30 °C 2.1: hydrogen / ethyl acetate / 60 - 65 °C / 7500.75 Torr 3.1: pivaloyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 5 °C 3.2: 0.08 h / 0 - 5 °C 4.1: ammonium hydroxide / water; dichloromethane / pH 8 - 10 View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 12 h / 20 °C 2.1: palladium 10% on activated carbon / 20 h / 22801.5 Torr 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 0.75 h / 0 °C 3.2: 20 °C View Scheme

1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazole-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide acetate salt (1188417-09-5) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
With ammonium hydroxide In dichloromethane; water at 25 - 35℃; for 0.166667h; pH=9.5;	55 g

(4-cyanophenyl)glycine (42288-26-6) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: dichloromethane / Reflux 2.1: dichloromethane / 4 h / Reflux 3.1: toluene / Dean-Stark; Reflux 3.2: 0.5 h / Reflux 4.1: ammonium hydroxide / dichloromethane; water / 0.17 h / 25 - 35 °C / pH 9.5 View Scheme
Multi-step reaction with 3 steps 1: dichloromethane / 20 - 25 °C / Inert atmosphere 2: toluene / 3 h / 50 °C 3: toluene / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.5 h / 20 °C 1.2: 20 °C 2.1: acetic acid / acetic acid butyl ester / 85 - 90 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 6 h / 0 - 5 °C / Large scale 1.2: 24 h / 20 °C / Large scale 2.1: acetic acid / dichloromethane / 10 h / 80 - 85 °C / Large scale 2.2: pH 9 / Large scale View Scheme

4-(2-imidazol-1-yl-2-oxoethylamino)benzonitrile → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dichloromethane / 4 h / Reflux 2.1: toluene / Dean-Stark; Reflux 2.2: 0.5 h / Reflux 3.1: ammonium hydroxide / dichloromethane; water / 0.17 h / 25 - 35 °C / pH 9.5 View Scheme

3-amino-4-[N-[2-(4-cyanophenylamino)acetyl]-N-methylamino]benzoic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene / Dean-Stark; Reflux 1.2: 0.5 h / Reflux 2.1: ammonium hydroxide / dichloromethane; water / 0.17 h / 25 - 35 °C / pH 9.5 View Scheme

methyl 3-methoxy-4-aminobenzoate (41608-64-4) → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 3.5 h / 0 - 25 °C 2: ethyl acetate / 12 h / 25 °C 3: 1,1'-carbonyldiimidazole; acetic acid / ethyl acetate / 6 h / 50 °C View Scheme

C27H26N6O6 → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
With 5% Pd(OH)2/C; hydrogen; acetic acid In ethyl acetate under 750.075 Torr;	14.9 mg

C27H29N7O4 → 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3)

Conditions	Yield
With acetic acid for 1.5h; Reflux;

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 3-({2-[(4-carbamimidoylphenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl ester

Conditions	Yield
Stage #1: 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With hydrogenchloride In ethanol at 35 - 42℃; Stage #2: With ammonium carbonate; ammonia In ethanol at 0 - 32℃;	96.61%
With lithium hexamethyldisilazane In tetrahydrofuran at -5 - 20℃; for 2h; Solvent;	95%
With hydrogenchloride In ethanol at 20℃;	92%

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 3-(2-(((4-cyanophenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propionic acid (212322-77-5)

Conditions	Yield
With sodium hydroxide In ethanol; water at 20℃; for 2h;	96.1%

ethanol (64-17-5) + 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 3-({2-[(4-ethoxycarbonimidoylphenylamino)methyl]1-methyl-1H-benzimidazol-5-carbonyl}pyridin-2-yl-amino)ethyl propanoate hydrochloride (1354727-65-3)

Conditions	Yield
With trichlorophosphate at 0 - 25℃;	93%
With hydrogenchloride at 10 - 35℃; for 24h;
With hydrogenchloride In chloroform; toluene at 10℃; for 24h; Solvent; Temperature;

benzenesulfonic acid (98-11-3) + 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → ethyl 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propanoate benzensulfonate

Conditions	Yield
Stage #1: benzenesulfonic acid; 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With hydrogenchloride In ethanol; water at -5 - 20℃; for 24h; Stage #2: With ammonia In ethanol; water at 0 - 20℃; for 24h; Temperature; Concentration;	92.6%

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazole-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride salt

Conditions	Yield
Stage #1: 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With hydrogenchloride In ethanol at 10 - 25℃; Stage #2: With ammonium hydroxide at 0 - 20℃;	81.9%
Stage #1: 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With hydrogenchloride In ethanol at 25℃; for 25h; Stage #2: With ammonium hydroxide In ethanol for 6h; pH=8.5 - 9.5;	77%
Stage #1: 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With hydrogenchloride; propionyl chloride; Ethyl propionate In ethanol; water at 10 - 40℃; for 10h; Pinner Amidine Synthesis; Large scale; Stage #2: With ammonium hydroxide In ethanol; water at 50℃; for 10h; pH=9; Solvent; Reagent/catalyst; Concentration; Large scale;	75.4%

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → C27H29N7O4 (658078-29-6)

Conditions	Yield
Stage #1: 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With hydrogenchloride In ethanol Stage #2: With hydroxylamine hydrochloride; triethylamine In ethanol	80%

diethyl ether (60-29-7) + 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 3-(2-(((4-cyanophenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propionic acid (212322-77-5)

Conditions	Yield
With sodium hydroxide In ethanol; water	78%

toluene-4-sulfonic acid (104-15-4) + 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-2-(ethoxycarbonylethyl)-amide p-toluenesulfonic acid salt (872728-85-3)

Conditions	Yield
Stage #1: toluene-4-sulfonic acid; 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With hydrogenchloride In ethanol at 25 - 30℃; for 20h; Autoclave; Large scale; Stage #2: With ammonia In ethanol at 20 - 30℃; for 2h; Autoclave; Large scale; Stage #3: With sodium hydroxide In ethanol; water at 20℃; for 1h; Autoclave; Large scale;	73.48%
With hydrogenchloride In ethanol at 0 - 17℃; for 18h; Temperature;	26.2 g

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic acid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide (658078-29-6)

Conditions	Yield
With hydroxylamine hydrochloride; triethylamine In dimethyl sulfoxide at 20 - 30℃; for 24h; Solvent; Reagent/catalyst; Temperature;	70%
With hydroxylamine hydrochloride; sodium ethanolate In ethanol at 0 - 58℃; for 24h;

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic acid (N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide

Conditions	Yield
Stage #1: 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With hydrogenchloride In ethanol at 0 - 20℃; for 5h; Stage #2: With hydroxylamine hydrochloride; triethylamine In ethanol at 0 - 20℃; for 2h;	61.5%

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → N-[[2-[[[4-(N'-hydroxycarbamimidoyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-(2-pyridyl)-β-alanine ethyl ester hydrochloride

Conditions	Yield
With hydroxylamine hydrochloride; triethylamine In methanol at 50 - 55℃; for 3h; Solvent; Temperature; Reagent/catalyst;	50%

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → dabigatran

Conditions	Yield
Multi-step reaction with 2 steps 1.1: HCl / ethanol / 0 °C 1.2: 71 percent / (NH4)2CO3 / ethanol / 20 °C 2.1: 91 percent / aq. NaOH / ethanol / 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethanol / 12 h / 20 °C 1.2: 5 h / 20 °C 2.1: sodium hydroxide; water / ethanol / 3 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 18 h / 10 - 15 °C 2.1: acetone / 2 h / 20 °C 3.1: potassium carbonate / water / 20 - 25 °C / pH Ca. 10 3.2: 8 h 4.1: sodium hydroxide / water; ethanol / 6 h View Scheme

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → dabigatran etexilate (211915-06-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: HCl / ethanol / 0 °C 1.2: 71 percent / (NH4)2CO3 / ethanol / 20 °C 2.1: aq. K2CO3 / tetrahydrofuran / 0.25 h / 20 °C 2.2: 51 percent / tetrahydrofuran / 1 h / 20 °C View Scheme

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → BrH*C27H26N6O3 (1046806-03-4)

Conditions	Yield
With hydrogen bromide In water; isopropyl alcohol at 7 - 38℃; for 1.33333h; pH=0.6 - 1.3; Industry scale;

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → dabigatran etexilate (211915-06-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: calcium(II) chloride dihydrate / ethanol / 0.33 h 1.2: 13 h / 0 - 30 °C 1.3: 10.5 h / 0 - 35 °C 2.1: ethanol / 6.75 h / 25 - 60 °C 3.1: potassium carbonate / acetonitrile; water / 0.25 h / 12 - 18 °C 3.2: 4.5 h / 12 - 18 °C View Scheme
Multi-step reaction with 3 steps 1.1: calcium(II) chloride dihydrate / ethanol / 0.33 h 1.2: 13 h / 0 - 30 °C 1.3: 10.5 h / 0 - 35 °C 2.1: ethanol / 6.75 h / 25 - 60 °C 3.1: potassium carbonate / acetonitrile; water / 0.25 h / 12 - 18 °C 3.2: 14.42 h / 12 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethanol; dichloromethane / 6 h / 15 - 30 °C 1.2: 15 - 30 °C 2.1: triethylamine / water; acetonitrile / 15 °C View Scheme

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / isopropyl alcohol / 1 h / 0 - 35 °C 2: hydrogenchloride / 24 h / 30 °C 3: ammonium carbonate / ethanol / 20 °C / Inert atmosphere View Scheme
Stage #1: 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester With calcium(II) chloride dihydrate In ethanol for 0.333333h; Stage #2: With hydrogenchloride at 0 - 30℃; for 13h; Stage #3: With ammonium formate; ammonium carbonate at 0 - 35℃; for 10h;	45 g

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → ethyl N-[(2-[(p-[ethoxyimidoyl]phenyl)amino]methyl)-1-methyl-1H-benzimidazole-5-carbonyl]-N-(2-pyridyl)-3-aminopropionate hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol / 1 h / 0 - 35 °C 2: hydrogenchloride / 24 h / 30 °C View Scheme

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → dabigatran etexilate (211915-06-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride / isopropyl alcohol / 1 h / 0 - 35 °C 2: hydrogenchloride / 24 h / 30 °C 3: ammonium carbonate / ethanol / 20 °C / Inert atmosphere 4: triethylamine / acetone / 1.5 h / 0 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol / 18 h / 0 - 17 °C 2: potassium carbonate / acetone; water / 1.5 h / 12 - 25 °C View Scheme
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethanol / 24 h / 20 °C 1.2: 10 - 20 °C 2.1: potassium carbonate / water; acetone / 10 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; triethylamine / dimethyl sulfoxide / 24 h / 20 - 30 °C 2.1: hydrogen; acetic acid / water / 24 h / 55 - 65 °C 2.2: 1 h 3.1: potassium carbonate / water; acetone / 10 - 20 °C View Scheme

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → ethyl N-[(2-[(p-cyanophenyl)amino]methyl)-1-methyl-1H-benzimidazole-5-carbonyl]-N-(2-pyridyl)-3-aminopropionate hydrochloride

Conditions	Yield
With hydrogenchloride In isopropyl alcohol at 0 - 35℃; for 1h;

Upstream product

• 212322-56-0 ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate 
• 218168-58-2 ethyl 2-((4-cyanophenyl)amino)acetate 
• 41608-64-4 methyl 3-methoxy-4-aminobenzoate 
• 42288-26-6 (4-cyanophenyl)glycine 
• 1188417-09-5 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazole-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide acetate salt 
• 103041-38-9 2-chloromethyl-1-methyl-1H-benzimidazole-5 ethyl acetate 
• 140-88-5 ethyl acrylate 
• 504-29-0 2-aminopyridine 
• 96-99-1 4-chloro-3-nitrobenzoate 
• 873-74-5 4-Aminobenzonitrile 
• 429659-01-8 ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate 
• 41263-74-5 4-(methylamino)-3-nitrobenzoic acid 
• 82357-48-0 4-methylamino-3-nitro-benzoic acid chloride 
• 948551-71-1 3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-pyridin-2-yl-amino)-ethyl propanoate 

Downstream Products

• 211915-06-9 dabigatran etexilate 
• 429658-95-7 3-({2-[(4-carbamimidoylphenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl ester 
• 872728-81-9 N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl] amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-(2-pyridinyl)-β-alanine ethyl ester methanesulfonate 
• 1381757-41-0 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate 
• 1354727-65-3 ethyl 3-[[2-[[ethoxy(imino)methylphenylamino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl]pyridin-2-yl-amino]propionate hydrochloride 
• 872728-85-3 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-2-(ethoxycarbonylethyl)-amide p-toluenesulfonic acid salt 
• 1408238-41-4 ethyl 2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-carboxylate 
• 211915-06-9 ethyl 3-(1-{2-[({4-[amino({[(hexyloxy)carbonyl]imino})methyl]phenyl}amino)methyl]-1-methyl-1H-1,3-benzodiazol-5-yl}-N-(pyridin-2-yl)formamido)propanoate 
• 658078-29-6 1-methyl-2-[4-(N-hydroxyamidino)-phenylaminomethyl]-benzimidazol-5-yl-carboxylic acid-(N-2-pyridyl-N-2-ethoxycarbonylethyl)-amide 

Relevant articles and documents

Preparation method of anticoagulant drug dabigatran etexilate and analogues thereof

The invention discloses a preparation method of an anticoagulant drug dabigatran etexilate and analogues thereof. The preparation method comprises the following steps: 3-[(3-amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionic acid ethyl ester (DGM1) and isopropyl 2-(4-cyanophenylamino)acetate (DGM2) which are taken as reaction initial raw materials undergo a docking reaction under the action ofan alkali reagent and a condensing agent to prepare an intermediate DG1; the intermediate DG1 reacts in an alcohol solvent to produce imino ester, and acid catalysis and ammonia reaction are carriedout to prepare a formamidine compound; an intermediate DG2 reacts with n-hexyl chloroformate under the action of the alkali reagent to remove one molecule of water and form an amido bond in order to obtain dabigatran etexilate; and the dabigatran etexilate analogues DG-D1 to DG-D4 are prepared from the dabigatran etexilate and its intermediate DG2. The preparation method of the dabigatran etexilate and analogues thereof has the advantages of short and feasible synthesis route, simplicity in operation, high product yield is high, and suitableness for large-scale industrial production.

Preparation method of dabigatran intermediate

The invention discloses a dabigatran intermediate preparation method which is as follows: a formula V compound as a raw material reacts with a formula VI compound to prepare a formula III compound, the formula III compound reacts with 4-amino cyanobenzene under the effect of an alkali to obtain a formula II compound, and then a target product formula I compound is obtained by transfer hydrogenation. The dabigatran intermediate preparation method is short and simple in steps, mild in conditions, high in total reaction yield, and suitable for industrial production.

Synthetic method for pradaxa key intermediate

The invention relates to a synthetic method for ethyl [2-[[(4-cyanophenyl)amino]-methyl] -1-methyl-1H-benzimidazol-5-yl]carbonyl] (pyridin-2-yl)amino]propanoate. According to the synthetic method, thereaction formula is as shown in the description. The synthetic method comprises the following steps that 1) a compound SM01 reacts with a coupling reagent CDI in a toluene solution; 2) after the reaction in the step 1) is finished, an obtained reaction solution is cooled, and an SM02 toluene solution is added for reaction; and 3) after the reaction is finished, acetic acid is added, and then thereaction is continued to the end. Compared with the prior art, the synthetic method has the advantages that a solvent is single and does not need to be replaced in the reaction process, the operationis simple and convenient, by-products are few, the yield is high and is 93-96%, a high-purity product of DB02 is easily obtained, the HPLC content is 99% or above, and the method is suitable for industrial production.