3543-73-5

Basic information

• Product Name: 1-Methyl-5-amino-1H-benzimidazole-2-butanoic acid ethyl ester
• Synonyms: 1-Methyl-5-amino-1H-benzimidazole-2-butanoic acid ethyl ester;ethyl 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate;4-(5-Amino-1-methyl-1H-benzoimidazol-2-yl)-butyric acidethylester;5-amino-1-methyl-2-Benzimidazolebutyric acid ethyl ester;Ethyl-4-(5-aMino-1-Methy-1H-benzo[d] iMidazol-2-yl)butanoate;5-AMino-1-Methyl-;4-[5-AMino-1-MethylbenziMidazol-2-yl]butanoic acid ethyl ester;1-Methyl-5-aMino-1H-benziMidazole-2-butanoic acid ethyl este
• CAS NO: 3543-73-5
• Molecular Formula: C₁₄H₁₉N₃O₂
• Molecular Weight: 261.323
• EINECS: 1533716-785-6
• Product Categories: Aromatics;Heterocycles;Intermediates
• Mol File: 3543-73-5.mol
• Article Data: 6

Chemical Properties

• Melting Point: 130-135°C
• Boiling Point: 471.6 °C at 760 mmHg
• Flash Point: 239 °C
• Appearance: Brown solid
• Density: 1.21 g/cm³
• Refractive Index: 1.59
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly)
• PKA: 6.73±0.10(Predicted)
• CAS DataBase Reference: 1-Methyl-5-amino-1H-benzimidazole-2-butanoic acid ethyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: 1-Methyl-5-amino-1H-benzimidazole-2-butanoic acid ethyl ester(3543-73-5)
• EPA Substance Registry System: 1-Methyl-5-amino-1H-benzimidazole-2-butanoic acid ethyl ester(3543-73-5)

Safety Data

• Hazardous Substances Data: 3543-73-5(Hazardous Substances Data)

Usage

Chemical Properties

Brown Solid

Uses

Different sources of media describe the Uses of 3543-73-5 differently. You can refer to the following data:
1. 1-Methyl-5-amino-1H-benzimidazole-2-butanoic Acid Ethyl Ester is a Bendamustine impurity.
2. Bendamustine

InChI:InChI=1/C14H19N3O2/c1-3-19-14(18)6-4-5-13-16-11-9-10(15)7-8-12(11)17(13)2/h7-9H,3-6,15H2,1-2H3

Synthetic route

4‐(1‐methyl‐5‐nitro‐1H‐benzoimidazol‐2‐yl)butyric acid ethyl ester (3543-72-4) → ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol; ethyl acetate at 20℃; for 16h;	98.3%
With 5% Pd/C-iron; hydrogen In ethanol under 3000.3 Torr;	87.5%
With 5%-palladium/activated carbon; hydrogen In methanol; acetic acid at 25℃; under 750.075 - 1500.15 Torr; for 15h;	77.8%

6-fluoro-3-nitroaniline (369-36-8) → ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / toluene / 4 h / 85 °C 1.2: 3 h / 75 °C 2.1: sulfuric acid / 10 h / Reflux 3.1: 5% Pd/C-iron; hydrogen / ethanol / 3000.3 Torr View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / 70 - 85 °C 2.1: water / 3 h / 75 °C 2.2: 55 - 60 °C 3.1: sulfuric acid / 10 h / Reflux 4.1: ferrous(II) sulfate heptahydrate; hydrogen; Iron(III) nitrate nonahydrate; 5% Pd/C / ethanol / 3000.3 Torr View Scheme

glutaric anhydride, (108-55-4) → ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / toluene / 4 h / 85 °C 1.2: 3 h / 75 °C 2.1: sulfuric acid / 10 h / Reflux 3.1: 5% Pd/C-iron; hydrogen / ethanol / 3000.3 Torr View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 4 h / 70 - 85 °C 2.1: water / 3 h / 75 °C 2.2: 55 - 60 °C 3.1: sulfuric acid / 10 h / Reflux 4.1: ferrous(II) sulfate heptahydrate; hydrogen; Iron(III) nitrate nonahydrate; 5% Pd/C / ethanol / 3000.3 Torr View Scheme

4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid (31349-48-1) → ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid / 10 h / Reflux 2: 5% Pd/C-iron; hydrogen / ethanol / 3000.3 Torr View Scheme

5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid (451459-95-3) → ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: water / 3 h / 75 °C 1.2: 55 - 60 °C 2.1: sulfuric acid / 10 h / Reflux 3.1: ferrous(II) sulfate heptahydrate; hydrogen; Iron(III) nitrate nonahydrate; 5% Pd/C / ethanol / 3000.3 Torr View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl‐4,6‐d2)butanoic‐2,2,4,4‐d4 acid hydrochloride

Conditions	Yield
With water; water-d2; hydrogen chloride at 180℃; for 1.5h; Microwave irradiation; Sealed tube;	93.5%

2,4-dinitrobenzoyl chloride (20195-22-6) + ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → ethyl 4-(5-(2,4-dinitrobenzamido)-1-methyl-1H-benzimidazol-2-yl)butanoate (1227860-30-1)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃;	83%

benzyl bromide (100-39-0) + ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → ethyl 4-(5-(dibenzylamino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 24h;	82.9%

oxirane (75-21-8) + ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → 4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester (3543-74-6)

Conditions	Yield
Stage #1: oxirane; ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate With sodium acetate trihydrate In water; acetic acid at 0 - 25℃; for 23h; Stage #2: With potassium carbonate In dichloromethane at 20 - 25℃;	78.53%
With acetic acid In water at -5 - 0℃;	78.5%
Stage #1: ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate With acetic acid In water at 0 - 5℃; Stage #2: oxirane In water at 0 - 20℃; for 1.5h;

oxirene (157-18-6) + ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → 4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester (3543-74-6)

Conditions	Yield
With sodium acetate; acetic acid In water at 0 - 25℃; for 23h; Concentration; Temperature; Time; Reagent/catalyst; Solvent;	78.53%

2-(2-bromoethoxy)ethan-1-ol (57641-66-4) + ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → C18H27N3O4

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 85℃;	66%

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) + 2-bromoethanol (540-51-2) → 4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester (3543-74-6)

Conditions	Yield
With calcium carbonate In acetonitrile at 80 - 90℃;	56.3%
With potassium carbonate In water at 69 - 70℃; for 13.5h; pH=4.2 - 5.5; Large scale;	343.5 g
With diammonium phosphate; potassium iodide In water at 65 - 70℃; pH=4.2 - 5.5; Reagent/catalyst; pH-value; Temperature;	17.2 g

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) + 2-chloro-ethanol (107-07-3) → 4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester (3543-74-6)

Conditions	Yield
With sodium carbonate; sodium iodide at 20 - 70℃;
With sodium carbonate; sodium iodide at 65 - 70℃;	10 g

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → lithium 4-[1-methyl-5-bis-(2-chloroethyl)-benzimidazolyl-2] butanoate

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium acetate; acetic acid / water / 23 h / 0 - 25 °C 2: thionyl chloride / dichloromethane / 6 h / Reflux 3: lithium hydroxide / water; acetone / 6 h / 15 - 20 °C View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → 4-{5-[bis(2-chloro-ethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid hydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium acetate; acetic acid / water / 23 h / 0 - 25 °C 2: thionyl chloride / dichloromethane / 6 h / Reflux 3: lithium hydroxide / water; acetone / 6 h / 15 - 20 °C 4: hydrogenchloride / water / 65 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium acetate trihydrate / water; acetic acid / 23 h / 0 - 25 °C 1.2: 20 - 25 °C 2.1: thionyl chloride / dichloromethane / 6 h / 35 - 45 °C 3.1: lithium hydroxide monohydrate / water; acetone / 15 - 20 °C 4.1: hydrogenchloride / water / 65 °C View Scheme
Multi-step reaction with 4 steps 1: calcium carbonate / acetonitrile / 80 - 90 °C 2: thionyl chloride / dichloromethane / 6 h / 35 - 45 °C 3: lithium hydroxide monohydrate / water; acetone / 15 - 20 °C 4: hydrogenchloride / water / 65 °C View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid ethyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium acetate; acetic acid / water / 23 h / 0 - 25 °C 2: thionyl chloride / dichloromethane / 6 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: calcium carbonate / acetonitrile / 80 - 90 °C 2: thionyl chloride / dichloromethane / 6 h / 35 - 45 °C View Scheme
Multi-step reaction with 2 steps 1: acetic acid / water / -5 - 0 °C 2: thionyl chloride / dichloromethane / 2 h / -5 - 20 °C View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → bendamustine hydrochloride (3543-75-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium carbonate; sodium iodide / 65 - 70 °C 2.1: thionyl chloride / dichloromethane / 0 °C / Reflux 2.2: 80 - 90 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / water / 13.5 h / 69 - 70 °C / pH 4.2 - 5.5 / Large scale 2: thionyl chloride / dichloromethane / 17 h / -1 - 22 °C 3: hydrogenchloride / water; acetone / 40 - 75 °C View Scheme
Multi-step reaction with 3 steps 1: diammonium hydrogenphosphate / water / 65 - 70 °C / pH 4.2 - 5.5 2: thionyl chloride / dichloromethane / 17 h / -1 - 22 °C 3: hydrogenchloride / water; acetone / 40 - 75 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium iodide; diammonium phosphate / water / 65 - 70 °C / pH 4.2 - 5.5 2.1: thionyl chloride / dichloromethane / 17 h / -1 - 22 °C 2.2: 75 °C View Scheme
Multi-step reaction with 3 steps 1: acetic acid / water / -5 - 0 °C 2: thionyl chloride / dichloromethane / 2 h / -5 - 20 °C 3: hydrogenchloride / water / 4 h / Reflux View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → bendamustine (16506-27-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium iodide; diammonium phosphate / water / 65 - 70 °C / pH 4.2 - 5.5 2: thionyl chloride / dichloromethane / 16 h / 5 - 20 °C View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → bendamustine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / water / 13.5 h / 69 - 70 °C / pH 4.2 - 5.5 / Large scale 2: thionyl chloride / dichloromethane / 17 h / -1 - 22 °C View Scheme
Multi-step reaction with 2 steps 1: diammonium hydrogenphosphate / water / 65 - 70 °C / pH 4.2 - 5.5 2: thionyl chloride / dichloromethane / 17 h / -1 - 22 °C View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) + 2-bromoethanol (540-51-2) → C20H32N3O5(1+)*Br(1-) + 4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester (3543-74-6)

Conditions	Yield
With diammonium hydrogenphosphate In water at 65 - 70℃; pH=4.2 - 5.5;

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → lithium 4-[1-methyl-5-bis-(2-chloroethyl)-benzimidazolyl-2]butanoate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium acetate trihydrate / water; acetic acid / 23 h / 0 - 25 °C 1.2: 20 - 25 °C 2.1: thionyl chloride / dichloromethane / 6 h / 35 - 45 °C 3.1: lithium hydroxide monohydrate / water; acetone / 15 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: calcium carbonate / acetonitrile / 80 - 90 °C 2: thionyl chloride / dichloromethane / 6 h / 35 - 45 °C 3: lithium hydroxide monohydrate / water; acetone / 15 - 20 °C View Scheme

chloroacetic acid (79-11-8) + ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid ethyl ester

Conditions	Yield
Stage #1: chloroacetic acid; ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate In tetrahydrofuran at 20℃; for 1.5h; Inert atmosphere; Stage #2: With borane-THF In tetrahydrofuran at 55 - 58℃; for 1.83333h;

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl‐4,6‐d2)butanoate‐2,2,4,4‐d4

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen chloride; water-d2; water / 1.5 h / 180 °C / Microwave irradiation; Sealed tube 2: thionyl chloride / 4.5 h / 0 - 50 °C View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → ethyl 4‐(5‐(bis (2‐hydroxyethyl)amino)‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl‐4,6‐d2)butanoate‐2,2,4,4‐d4

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen chloride; water-d2; water / 1.5 h / 180 °C / Microwave irradiation; Sealed tube 2: thionyl chloride / 4.5 h / 0 - 50 °C 3: acetic acid / water-d2 / 19 h / 0 - 25 °C View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → C18H19(2)H6Cl2N3O2

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen chloride; water-d2; water / 1.5 h / 180 °C / Microwave irradiation; Sealed tube 2: thionyl chloride / 4.5 h / 0 - 50 °C 3: acetic acid / water-d2 / 19 h / 0 - 25 °C 4: thionyl chloride / dichloromethane / 10 h / 0 - 25 °C View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → 4‐(5‐(bis(2‐chloroethyl)amino)‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl‐4,6‐d2)butanoic‐2,2,4,4‐d4 acid hydrochloride

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogen chloride; water-d2; water / 1.5 h / 180 °C / Microwave irradiation; Sealed tube 2: thionyl chloride / 4.5 h / 0 - 50 °C 3: acetic acid / water-d2 / 19 h / 0 - 25 °C 4: thionyl chloride / dichloromethane / 10 h / 0 - 25 °C 5: hydrogen chloride; water / water-d2 / 2 h / Reflux View Scheme

2-(2-Chloroethoxy)ethanol (628-89-7) + ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → C18H27N3O4

Conditions	Yield
With sodium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃;

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → C20H31N3O5

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate; potassium iodide / N,N-dimethyl-formamide / 80 °C 2: acetic acid / water / 24 h / 5 - 10 °C / Sealed tube View Scheme
Multi-step reaction with 2 steps 1: sodium carbonate; potassium iodide / N,N-dimethyl-formamide / 80 °C 2: sodium ethanolate / ethanol / 48 h / 0 - 10 °C / Sealed tube View Scheme
Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 85 °C 2: acetic acid / water / 24 h / 5 - 10 °C / Sealed tube View Scheme
Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 85 °C 2: sodium ethanolate / ethanol / 48 h / 0 - 10 °C / Sealed tube View Scheme

ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate (3543-73-5) → C18H25Cl2N3O3*ClH

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium carbonate; potassium iodide / N,N-dimethyl-formamide / 80 °C 2.1: acetic acid / water / 24 h / 5 - 10 °C / Sealed tube 3.1: thionyl chloride; chloroform / chloroform / 0 - 50 °C 3.2: 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium carbonate; potassium iodide / N,N-dimethyl-formamide / 80 °C 2.1: sodium ethanolate / ethanol / 48 h / 0 - 10 °C / Sealed tube 3.1: thionyl chloride; chloroform / chloroform / 0 - 50 °C 3.2: 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 85 °C 2.1: acetic acid / water / 24 h / 5 - 10 °C / Sealed tube 3.1: thionyl chloride; chloroform / chloroform / 0 - 50 °C 3.2: 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 85 °C 2.1: sodium ethanolate / ethanol / 48 h / 0 - 10 °C / Sealed tube 3.1: thionyl chloride; chloroform / chloroform / 0 - 50 °C 3.2: 80 °C View Scheme

Upstream product

• 369-36-8 6-fluoro-3-nitroaniline 
• 108-55-4 glutaric anhydride, 
• 31349-48-1 4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid 
• 451459-95-3 5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid 
• 3543-72-4 4‐(1‐methyl‐5‐nitro‐1H‐benzoimidazol‐2‐yl)butyric acid ethyl ester 

Downstream Products

• 1227860-30-1 ethyl 4-(5-(2,4-dinitrobenzamido)-1-methyl-1H-benzimidazol-2-yl)butanoate 
• 3543-74-6 4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester 
• 3543-75-7 bendamustine hydrochloride 
• 16506-27-7 bendamustine 

Relevant articles and documents

High-purity bendamustine hydrochloride intermediate preparation method

The invention provides a high-purity bendamustine hydrochloride intermediate preparation method, wherein the intermediate is 5-amino-1-methyl-1H-2-benzimidazolebutyric acid ethyl ester, and the preparation method is characterized in that the mixed solvent of methanol and ethyl acetate is used. According to the present invention, with the preparation method, the impurities generated by the reduction reaction can be effectively reduced so as to obtain the high-purity intermediate and the final product bendamustine hydrochloride and reduce the difficulty in the industrial purification.

PROCESS FOR THE PREPARATION OF BENDAMUSTINE

The present invention relates to a method for preparation of alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7) from 2-fluoro-5-nitroaniline, comprising the steps of: (a) conversion of 2-fluoro-5-nitroaniline to 5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid (1) using glutaric anhydride, conversion of compound (1) to methylammonium 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoate (2) using methylamine; conversion of compound (2) to 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoic acid (3) and condensation of compound (3) to 4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid (4); (b) esterification of the product (4) of step a) to alkyl 4-(1-methyl-5-nitro1H-benzimidazol-2-yl)butanoate (5); (c) reduction of the product of step b) to alkyl 4-(5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (6), and (d) conversion of the product of step c) to alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7)

Process for Preparation of Intermediates of Bendamustine

The present invention relates to a process for the preparation of 4-{5-{Bis-(2-hydroxyl-ethyl)-amino}-1-methyl-1H-Benzoimidazol-2yl}-butyric acid alkyl ester of formula IV, a key intermediate in the process for the preparation of Bendamustine HCl (I)