42288-26-6

Basic information

• Product Name: N-(4-CYANO-PHENYL)-GLYCINE
• Synonyms: N-(4-CYANO-PHENYL)-GLYCINE;Dabigatran Intermediate 2;[(4-Cyanophenyl)aMino]acetic Acid;4-(((Carboxy)Methyl)aMino)benzonitrile;N-(p-Cyanophenyl)glycine;Dabigatran pharMaceutical interMediate;Glycine, N-(4-cyanophenyl)-;Dabigatran Etexilate Intermediate 2
• CAS NO: 42288-26-6
• Molecular Formula: C₉H₈N₂O₂
• Molecular Weight: 176.17202
• EINECS: 459-560-3
• Product Categories: Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;For API's Production;Intermediate of Dabigatran
• Mol File: 42288-26-6.mol
• Article Data: 17

Chemical Properties

• Melting Point: 237 °C(dec.)
• Boiling Point: 447.2 °C at 760 mmHg
• Flash Point: 224.3 °C
• Appearance: Off-white solid
• Density: 1.3 g/cm³
• Vapor Pressure: 8.8E-09mmHg at 25°C
• Refractive Index: 1.593
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: Dichloromethane (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 3.81±0.10(Predicted)
• CAS DataBase Reference: N-(4-CYANO-PHENYL)-GLYCINE(CAS DataBase Reference)
• NIST Chemistry Reference: N-(4-CYANO-PHENYL)-GLYCINE(42288-26-6)
• EPA Substance Registry System: N-(4-CYANO-PHENYL)-GLYCINE(42288-26-6)

Safety Data

• Hazardous Substances Data: 42288-26-6(Hazardous Substances Data)

Usage

Description

Dabigatran etexilate is a novel synthetic direct thrombin inhibitor, a prodrug of dabigatran, a non-peptide thrombin inhibitor. Dabigatran etexilate intermediate II is an impurity produced during the preparation of dabigatran etexilate.

Physical properties

N-(4-Cyanophenyl)glycine is a off-white Solid.

Uses

N-(4-Cyanophenyl)-glycine (cas# 42288-26-6) is a compound useful in organic synthesis.

InChI:InChI=1/C9H8N2O2/c10-5-7-1-3-8(4-2-7)11-6-9(12)13/h1-4,11H,6H2,(H,12,13)

Synthetic route

bromoacetic acid (79-08-3) + 4-Aminobenzonitrile (873-74-5) → (4-cyanophenyl)glycine (42288-26-6)

Conditions	Yield
In water at 100 - 110℃; for 3h;	88%
In water at 100℃; for 16h;
In water at 20 - 100℃; for 16.4h;
In water at 100℃; for 5h;
In water at 100℃;

4-bromobenzenecarbonitrile (623-00-7) + glycine (56-40-6) → (4-cyanophenyl)glycine (42288-26-6)

Conditions	Yield
With potassium phosphate; copper(l) iodide; N-((1-oxy-pyridin-2-yl)methyl)oxalamic acid In water; dimethyl sulfoxide at 25℃; for 48h; Schlenk technique; Inert atmosphere; Sealed tube; chemoselective reaction;	88%

sodium monochloroacetic acid (3926-62-3) + 4-Aminobenzonitrile (873-74-5) → (4-cyanophenyl)glycine (42288-26-6)

Conditions	Yield
In water for 6.5h; Product distribution / selectivity; Reflux;	73.2%
With water at 0℃; Product distribution / selectivity; Reflux;	73.2%
Stage #1: sodium monochloroacetic acid; 4-Aminobenzonitrile With tetrabutylammomium bromide; sodium hydrogencarbonate; potassium iodide In water at 90 - 95℃; for 24h; Stage #2: With ammonia In water at 20 - 30℃; for 0.333333h; pH=7.5; Stage #3: With hydrogenchloride In water at 20 - 30℃; for 3h; pH=2.5; Product distribution / selectivity;
With tetrabutylammomium bromide; sodium hydrogencarbonate; potassium iodide In water at 90 - 95℃; for 24h;	131 g
With tetrabutylammomium bromide; sodium hydrogencarbonate; potassium iodide In water at 85 - 90℃; for 24h;	120 g

chloroacetic acid (79-11-8) + 4-Aminobenzonitrile (873-74-5) → (4-cyanophenyl)glycine (42288-26-6)

Conditions	Yield
In water Reflux;	73%
In water Heating / reflux;	58%
In water Reflux;	47%
With water

Glyoxilic acid (298-12-4) + 4-Aminobenzonitrile (873-74-5) → (4-cyanophenyl)glycine (42288-26-6)

Conditions	Yield
With sodium cyanoborohydride for 2h; Milling;	56%

(4-cyanophenylamino)-acetic acid tert-butyl ester (144656-11-1) → (4-cyanophenyl)glycine (42288-26-6)

Conditions	Yield
With methoxybenzene; trifluoroacetic acid
With trifluoroacetic acid In dichloromethane for 24h; Ambient temperature;

4-Aminobenzonitrile (873-74-5) → (4-cyanophenyl)glycine (42288-26-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / dimethylformamide / 16 h / 80 °C 2: TFA / CH2Cl2; various solvent(s) / 24 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: K2CO3 2: TFA, anisole View Scheme

(R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone (253796-98-4) + (4-cyanophenyl)glycine (42288-26-6) + 1,1'-carbonyldiimidazole (530-62-1) → (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert-butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Conditions	Yield
In tetrahydrofuran; acetic acid	100%

(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-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-pyridin-2-yl-amino)-ethyl propanoate (948551-71-1)

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 5℃; for 6h; Large scale; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In dichloromethane at 20℃; for 24h; Solvent; Reagent/catalyst; Large scale;	99.3%
Stage #1: (4-cyanophenyl)glycine With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 0.5h; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In tetrahydrofuran at 20℃;	93.8%
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 0 - 10℃; for 0.5h; Large scale; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In tetrahydrofuran at 20 - 25℃; for 6h; Large scale;	84.33%
Stage #1: (4-cyanophenyl)glycine With 1,1'-carbonyldiimidazole In tetrahydrofuran at 50℃; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In tetrahydrofuran for 24h; Heating; Further stages.;

(4-cyanophenyl)glycine (42288-26-6) + (piperidin-4-yl)carbamic acid tert-butyl ester (73874-95-0) → tert-butyl N-[1-[2-(4-cyanoanilino)acetyl]-4-piperidyl]carbamate

Conditions	Yield
With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	99%

(4-cyanophenyl)glycine (42288-26-6) + tert-butyl N-(4-piperidinylmethyl)carbamate (135632-53-0) → tert-butyl N-[[1-[2-(4-cyanoanilino)acetyl]-4-piperidyl]methyl]carbamate

Conditions	Yield
With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	98%

(4-cyanophenyl)glycine (42288-26-6) → 3-({3-[2-(4-Cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-phenyl-amino)-propionic acid methyl ester (1315605-52-7)

Conditions	Yield
With 1,1'-carbonyldiimidazole In tetrahydrofuran	97%

4-[1-(pyrrolidin-1-yl-carbonyl)cyclopropyl]-2-nitro-N-methylaniline (253431-25-3) + 4-[1-(N-(3-ethoxycarbonyl-propionyl)-N-cyclopentyl-amino)cyclopropyl]-2-amino-N-methyl-aniline, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate + (4-cyanophenyl)glycine (42288-26-6) → 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)-cyclopropyl]-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl-aniline

Conditions	Yield
With triethylamine In N-methyl-acetamide	96%

(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-amino-4-butyl aminobenzoyl)(3-chloro-4-fluorophenyl)amino]propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-[{1-butyl-2-[(4-cyanophenylamino)methyl]-1H-benzoimidazole-5-carbonyl} (3-chloro-4-fluorophenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide In tetrahydrofuran for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-butyl aminobenzoyl)(3-chloro-4-fluorophenyl)amino]propionic acid ethyl ester In tetrahydrofuran at 20℃; for 4h; Stage #3: With acetic acid for 3h; Reflux;	95%

3-[(3-amino-4-ethylamino-benzoyl)-(3,5-difluorophenyl)-amino]-propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → ethyl 3-(2-(((4-cyanophenyl)amino)methyl)-N-(3,5-difluorophenyl)-1-ethyl-1H-benzo[d]imidazole-5-carboxamido)propanoate

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.583333h; Cooling with ice; Stage #2: 3-[(3-amino-4-ethylamino-benzoyl)-(3,5-difluorophenyl)-amino]-propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; Stage #3: With acetic acid at 120℃; for 2 - 3h;	93%

(4-cyanophenyl)glycine (42288-26-6) + acetic acid (64-19-7) + ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazole-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide acetate salt (1188417-09-5)

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.666667h; Inert atmosphere; Reflux; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In tetrahydrofuran for 5h; Inert atmosphere; Reflux; Stage #3: acetic acid In tetrahydrofuran for 1h; Reflux;	92%

(4-cyanophenyl)glycine (42288-26-6) + toluene-4-sulfonic acid (104-15-4) + ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide p-toluenesulfonate

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With pivaloyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 5℃; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In tetrahydrofuran at 0 - 5℃; for 0.0833333h; Stage #3: toluene-4-sulfonic acid Further stages;	89.59%
Stage #1: (4-cyanophenyl)glycine With Imidazole hydrochloride; 1,1'-carbonyldiimidazole In dichloromethane at 35 - 40℃; for 1h; Inert atmosphere; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In dichloromethane for 1h; Inert atmosphere; Reflux; Stage #3: toluene-4-sulfonic acid In acetic acid butyl ester at 85 - 90℃; for 1h; Solvent; Inert atmosphere;	15.8 g

ethyl 3-(3-amino-4-(ethylamino)-N-(2-fluorophenyl)-benzamido)propanoate + (4-cyanophenyl)glycine (42288-26-6) → ethyl 3-(2-(((4-cyanophenyl)amino)methyl)-1-ethyl-N-(2-fluorophenyl)-1H-benzo[d]imidazole-5-carboxamido)-propanoate

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.583333h; Cooling with ice; Stage #2: ethyl 3-(3-amino-4-(ethylamino)-N-(2-fluorophenyl)-benzamido)propanoate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; Stage #3: With acetic acid at 120℃; for 2 - 3h;	89%

(4-cyanophenyl)glycine (42288-26-6) + 3-[(3-amino-4-methylaminobenzoyl)-(2-methoxyphenyl)amino]-propionic acid ethyl ester → 3-({2-[(4-cyanophenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-(2-methoxyphenyl)amino)propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-methylaminobenzoyl)-(2-methoxyphenyl)amino]-propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 5h;	89%

ethyl 5-[3-amino-4-(ethylamino)phenyl]-4-(2,3-dimethylphenyl)-5-oxopentanoate + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(2,3-dimethylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: ethyl 5-[3-amino-4-(ethylamino)phenyl]-4-(2,3-dimethylphenyl)-5-oxopentanoate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;	87.6%

3-[(3-amino-4-ethylaminobenzoyl)-(2,3-dimethylphenyl)amino]propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(2,3-dimethylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-ethylaminobenzoyl)-(2,3-dimethylphenyl)amino]propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h;	87.6%

3-[(3-amino-4-ethylaminobenzoyl)-(4-fluoro-3-methylphenyl)amino]propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(4-fluoro-3-methylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-ethylaminobenzoyl)-(4-fluoro-3-methylphenyl)amino]propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h;	87.6%

tert-butyl N-[(4-fluoropiperidin-4-yl)methyl]carbamate (871022-62-7) + (4-cyanophenyl)glycine (42288-26-6) → tert-butyl N-[[1-[2-(4-cyanoanilino)acetyl]-4-fluoro-4-piperidyl]methyl]carbamate

Conditions	Yield
With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	87%

3-[(3-amino-4-ethylamino-benzoyl)-(3,5-dimethylphenyl)-amino]-propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(3,5-dimethylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-ethylamino-benzoyl)-(3,5-dimethylphenyl)-amino]-propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h;	86.1%

3-[(3-chloro-4-methyl amino benzoyl)(3-chloro-4-fluorophenyl)amino]propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-((3-chloro-4-fluorophenyl){2-[(4-cyanophenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}amino)propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide In tetrahydrofuran for 0.5h; Cooling with ice; Stage #2: 3-[(3-chloro-4-methyl amino benzoyl)(3-chloro-4-fluorophenyl)amino]propionic acid ethyl ester In tetrahydrofuran at 20℃; for 4h; Stage #3: With acetic acid for 3h; Reflux;	86%

ethyl 3-amino-4-(methylamino)benzoate (66315-23-9) + (4-cyanophenyl)glycine (42288-26-6) → C19H20N4O3

Conditions	Yield
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 10 - 20℃;	86%

3-[(3-amino-4-ethylaminobenzoyl)-(3-fluoro-4-methylphenyl)amino]propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(3-fluoro-4-methylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-ethylaminobenzoyl)-(3-fluoro-4-methylphenyl)amino]propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h;	85.8%

ethyl 5-[3-amino-4-(ethylamino)phenyl]-4-(2,4-dimethylphenyl)-5-oxopentanoate + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(2,4-dimethylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: ethyl 5-[3-amino-4-(ethylamino)phenyl]-4-(2,4-dimethylphenyl)-5-oxopentanoate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;	85.5%

3-[(3-amino-4-ethylamino-benzoyl)-(3,4-dimethylphenyl)-amino]-propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}-(3,4-dimethyl-phenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-ethylamino-benzoyl)-(3,4-dimethylphenyl)-amino]-propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h;	85.5%

3-[(3-amino-4-ethylamino-benzoyl)-(2,4-dimethylphenyl)-amino]-propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(2,4-dimethylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-ethylamino-benzoyl)-(2,4-dimethylphenyl)-amino]-propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h;	85.4%

methanesulfonic acid (75-75-2) + (4-cyanophenyl)glycine (42288-26-6) + ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate mesylate

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In tetrahydrofuran at 30 - 35℃; Stage #3: methanesulfonic acid Further stages;	85%
Stage #1: (4-cyanophenyl)glycine With 1,1'-carbonyldiimidazole In tetrahydrofuran at 25 - 35℃; for 3h; Stage #2: ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate In tetrahydrofuran at 25 - 35℃; for 24h; Stage #3: methanesulfonic acid In acetone at 0 - 10℃; for 3h; Concentration; Temperature;	220 g

3-[(3-amino-4-ethylaminobenzoyl)(2,5-dimethyl-phenyl)amino]propionic acid ethyl ester + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(2,5-dimethylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3-[(3-amino-4-ethylaminobenzoyl)(2,5-dimethyl-phenyl)amino]propionic acid ethyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h;	84.5%

ethyl 5-[3-amino-4-(ethylamino)phenyl]-4-(2,5-dimethylphenyl)-5-oxopentanoate + (4-cyanophenyl)glycine (42288-26-6) → 3-[{2-[(4-cyanophenylamino)methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}(2,5-dimethylphenyl)amino]propionic acid ethyl ester

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: ethyl 5-[3-amino-4-(ethylamino)phenyl]-4-(2,5-dimethylphenyl)-5-oxopentanoate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;	84.2%

ethyl 5-[3-amino-4-(ethylamino)phenyl]-4-(3-methylphenyl)-5-oxopentanoate + (4-cyanophenyl)glycine (42288-26-6) → ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-ethyl-1H-benzimidazol-5-yl)carbonyl](3-methylphenyl)amino}propanoate

Conditions	Yield
Stage #1: (4-cyanophenyl)glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: ethyl 5-[3-amino-4-(ethylamino)phenyl]-4-(3-methylphenyl)-5-oxopentanoate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;	83.7%

Upstream product

• 79-11-8 chloroacetic acid 
• 873-74-5 4-Aminobenzonitrile 
• 144656-11-1 (4-cyanophenylamino)-acetic acid tert-butyl ester 
• 79-08-3 bromoacetic acid 
• 3926-62-3 sodium monochloroacetic acid 
• 623-00-7 4-bromobenzenecarbonitrile 
• 56-40-6 glycine 
• 298-12-4 Glyoxilic acid 

Downstream Products

• 211915-84-3 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester 
• 211915-73-0 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide 
• 212322-13-9 1-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxy-carbonylpropyl)-amide 
• 211915-82-1 1-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide 
• 1188417-09-5 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazole-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide acetate salt 
• 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 
• 1381757-44-3 2-(N-(3-ethoxy-3-oxopropyl)-2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)pyridine-1-oxide 
• 1422435-39-9 ethyl 2-[[4-(aminoiminomethyl)phenylamino]methyl]-1-methyl-1H-benzimidazole-5-carboxylate hydrochloride 
• 1422469-70-2 ethyl 3-[[2-[(4-cyanophenylamino)methyl]-1-methyl-1H-benzimidazole-5-carbonyl]pyridin-2-yl-amino]propionate succinic acid 
• 1354727-65-3 ethyl 3-[[2-[[ethoxy(imino)methylphenylamino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl]pyridin-2-yl-amino]propionate hydrochloride 
• 1427571-33-2 C₂₁H₂₄N₄O₃*ClH 

Relevant articles and documents

Mechanosynthesis of sydnone-containing coordination complexes

N-Phenyl-4-(2-pyridinyl) sydnone was shown to act as a four-electron donor N,O-ligand in unprecedented coordination complexes featuring three different metallic centers (Co, Cu, and Zn). Starting with various anilines, the use of a ball-mill efficiently enabled the synthesis of N-arylglycines, subsequent nitrosylation and cyclization into sydnones, and further metalation.

Design, synthesis, anticoagulant activity evaluation and molecular docking studies of a class of N -ethyl dabigatran derivatives

A class of N-ethyl dabigatran derivatives was designed based on pharmacological strategies for inhibition of thrombin activity and the structure-activity relationship studies of the previous dabigatran derivatives. Activities of these novel compounds were predicted based on CoMFA model, and most of the compounds had comparable predicted activity with dabigatran. All of screened compounds were synthesized and characterized by 1HNMR13C NMR and HRMS. Subsequently, these compounds were evaluated inhibitory activity on thrombin. Among these compounds, 9a-9e, 9h, 9l-9n and 9p exhibited comparable inhibitory activity to dabigatran (IC50 Combining double low line 1.20 nM), additionally, compound 9p (IC50 Combining double low line 0.96 nM) exhibited better inhibitory activity than dabigatran. Moreover, compound 9p also exhibited a fairly good inhibitory activity for arteriovenous thrombosis with inhibition rate of (85.35 ± 0.72) %, which was comparable to that of dabigatran (85.07 ± 0.61) %. These results, along with related molecular docking studies, could provide an important basis for further development of compound 9p as a potent thrombin inhibitor.

Process For The Preparation Of Benzimidazole Derivatives And Salts Thereof

Provided are novel salts of benzimidazole derivatives, preferably salts of benzimidazole derivatives which are useful intermediates in the synthesis of pure 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and its salts.