16506-27-7

Basic information

• Product Name: Bendamustine
• Synonyms: 5-(Bis(2-chloroethyl)amino)-1-methyl-2-benzimidazolebutyric acid;5-[Bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazole-2-butanoic acid;Bendamustine;4-(5-(bis(2-chloroethyl)aMino)-1-Methyl-1H-benzo[d]iMidazol-2-yl)butanoic acid;1H-BenziMidazole-2-butanoicacid, 5-[bis(2-chloroethyl)aMino]-1-Methyl-;-1-methyl-1H-benzo[d]imidazol-2-yl);4-(5-(Bis(2-chloroethyl);4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid
• CAS NO: 16506-27-7
• Molecular Formula: C₁₆H₂₁Cl₂N₃O₂
• Molecular Weight: 358.26
• Mol File: 16506-27-7.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 585.166 °C at 760 mmHg
• Flash Point: 307.697 °C
• Appearance: /
• Density: 1.318 g/cm³
• Vapor Pressure: 1.55E-14mmHg at 25°C
• Refractive Index: 1.599
• PKA: 4.50±0.10(Predicted)
• CAS DataBase Reference: Bendamustine(CAS DataBase Reference)
• NIST Chemistry Reference: Bendamustine(16506-27-7)
• EPA Substance Registry System: Bendamustine(16506-27-7)

Safety Data

• Hazardous Substances Data: 16506-27-7(Hazardous Substances Data)

Usage

Uses

Treatment of hematologic cancer, especially non-Hodgkin’s lymphoma.

Brand name

Ribomustine (Amcis AG, Switzerland).

Enzyme inhibitor

This nitrogen mustard and anticancer drug (FWfree-acid = 358.26 g/mol; CAS 16506-27-7), also known by its code name SDX-105, its trade names Treanda?, Treakisym?, Ribomustin?, and Levact?, as well as by its systematic name 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2- yl]butanoic acid, is a relatively nonspecific DNA alkylating agent that causes intra- and inter-strand cross-links. Bendamustine is used in the treatment of chronic lymphocytic leukemia (CLL), Hodgkin’s disease, nonHodgkin’s lymphoma, multiple myeloma and lung cancer. Pharmacokinetics: After intravenous infusion, >95% of the drug becomes protein-bound, mainly to albumin; however, only free bendamustine is active. Bendamustine is metabolized by liver cytochrome p450, and elimination (renal) is biphasic, with an initial half-life of 6–10 minutes and a terminal half-life of approximately 30 minutes.

InChI:InChI=1/C16H21Cl2N3O2/c1-20-14-6-5-12(21(9-7-17)10-8-18)11-13(14)19-15(20)3-2-4-16(22)23/h5-6,11H,2-4,7-10H2,1H3,(H,22,23)

Synthetic route

bendamustine hydrochloride (3543-75-7) → bendamustine (16506-27-7)

Conditions	Yield
With triethylamine In methanol other reagent;	89%

4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester (3543-74-6) → bendamustine (16506-27-7)

Conditions	Yield
With thionyl chloride In dichloromethane at 5 - 20℃; for 16h;	73%

4-{5-[bis(2-chloro-ethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid hydrochloride → bendamustine (16506-27-7)

Conditions	Yield
With sodium hydroxide In water

4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid ethyl ester → bendamustine (16506-27-7)

Conditions	Yield
Stage #1: 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid ethyl ester With water Alkaline conditions; Stage #2: With hydrogenchloride In water pH=~ 6 - ~ 7;

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

6-fluoro-3-nitroaniline (369-36-8) → bendamustine (16506-27-7)

Conditions	Yield
Multi-step reaction with 5 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 4.1: potassium iodide; diammonium phosphate / water / 65 - 70 °C / pH 4.2 - 5.5 5.1: thionyl chloride / dichloromethane / 16 h / 5 - 20 °C View Scheme

glutaric anhydride, (108-55-4) → bendamustine (16506-27-7)

Conditions	Yield
Multi-step reaction with 5 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 4.1: potassium iodide; diammonium phosphate / water / 65 - 70 °C / pH 4.2 - 5.5 5.1: thionyl chloride / dichloromethane / 16 h / 5 - 20 °C View Scheme

4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid (31349-48-1) → bendamustine (16506-27-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / 10 h / Reflux 2: 5% Pd/C-iron; hydrogen / ethanol / 3000.3 Torr 3: potassium iodide; diammonium phosphate / water / 65 - 70 °C / pH 4.2 - 5.5 4: thionyl chloride / dichloromethane / 16 h / 5 - 20 °C View Scheme

4‐(1‐methyl‐5‐nitro‐1H‐benzoimidazol‐2‐yl)butyric acid ethyl ester (3543-72-4) → bendamustine (16506-27-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 5% Pd/C-iron; hydrogen / ethanol / 3000.3 Torr 2: potassium iodide; diammonium phosphate / water / 65 - 70 °C / pH 4.2 - 5.5 3: thionyl chloride / dichloromethane / 16 h / 5 - 20 °C View Scheme

bendamustine (16506-27-7) → 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butan-1-ol (1221157-14-7)

Conditions	Yield
Stage #1: bendamustine With borane-THF In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: With water In tetrahydrofuran at 0℃;	86%

1-Tetradecanol (112-72-1) + bendamustine (16506-27-7) → 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid tetradecyl ester (1609623-05-3)

Conditions	Yield
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 27℃; Inert atmosphere;	83.4%

2-(morpholin-4-yl)ethanol (622-40-2) + bendamustine (16506-27-7) → 2-morpholinoethyl 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	82%

bendamustine (16506-27-7) → 4-<1-Methyl-5-benzimidazolyl-(2)>butansaeure (109882-30-6) + 4-[5-[(2-chloroethyl)-(2-hydroxy-ethyl)amino]-1-methyl-benzimidazo-2-yl]-butanoic acid (109882-27-1)

Conditions	Yield
With water at 37℃; for 8h;	A 81.6% B 14.7%
With water at 37℃; for 2h;	A 18.8% B 36.8%

ciprofloxacin (85721-33-1) + bendamustine (16506-27-7) → C33H37Cl2FN6O4*ClH (1318338-83-8)

Conditions	Yield
Stage #1: bendamustine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.25h; Stage #2: ciprofloxacin In dichloromethane at 20℃; for 1h;	73%

C19H32N4O6 (1297582-71-8) + bendamustine (16506-27-7) → C51H70Cl4N10O8

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 25h; Steglich reaction;	72.5%

1-(2-hydroxyethyl)-1H-pyrrole-2,5-dione (1585-90-6) + bendamustine (16506-27-7) → 2-{4-[6-bis(2-chloroethyl)amino-3-methylbenzo[d]imidazol-2-yl]butanoyl}oxyethylmaleimide (1297582-82-1)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 25h; Steglich reaction;	70.1%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; Steglich reaction;
With O-[(cyano(ethoxycarbonyl)methylidene)amino]-1,1,3,3-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere;	1.08 g

bendamustine (16506-27-7) + 5-Fluoro-2'-deoxyuridine (50-91-9) → C25H30Cl2FN5O6

Conditions	Yield
Stage #1: 5-Fluoro-2'-deoxyuridine With dmap; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: bendamustine In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere;	69%

(5R,5aR,8aS,9S)-9-amino-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,5a,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one (117507-84-3) + bendamustine (16506-27-7) → 4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-1,3-benzodiazol-2-yl}-N-[(10S,11S,15R,16R)-16-(4-hydroxy-3,5-dimethoxyphenyl)-14-oxo-4,6,13-trioxatetracyclo[7.7.0.03,7.011,15]hexadeca-1,3(7),8-trien-10-yl]butanamide

Conditions	Yield
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	65%

1-dodecyl alcohol (112-53-8) + bendamustine (16506-27-7) → 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid dodecyl ester (1456608-94-8)

Conditions	Yield
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20 - 27℃; Inert atmosphere;	59%

C24H42N4O6 (1297582-73-0) + bendamustine (16506-27-7) → C56H80Cl4N10O8

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 25h; Steglich reaction;	56.7%

13-(2-hydroxy)ethoxymatrine + bendamustine (16506-27-7) → 13-[2-(4-[5-[bis-(2-chloroethyl)amino]-1-methyl-2-benzoimidazole]butyrate)ethoxy]matrine

Conditions	Yield
With sulfuric acid In toluene at 125 - 130℃; for 5.5h;	53%

N-[(10S,11S,15R,16R)-16-(4-hydroxy-3,5-dimethoxyphenyl)-14-oxo-4,6,13-trioxatetracyclo[7.7.0.03,7.011,15]hexadeca-1,3(7),8-trien-10-yl]-2-(piperazin-1-yl)acetamide + bendamustine (16506-27-7) → 2-[4-(4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-1,3-benzodiazol-2-yl}butanoyl)piperazin-1-yl]-N-[(10S,11S,15R,16R)-16-(4-hydroxy-3,5-dimethoxyphenyl)-14-oxo-4,6,13-trioxatetracyclo[7.7.0.03,7.011,15]hexadeca-1,3(7),8-trien-10-yl]acetamide

Conditions	Yield
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	52%

13-(2-amino)ethoxymatrine + bendamustine (16506-27-7) → 13-[2-(4-{5-[bis-(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butylacetamido)ethoxy]matrine

Conditions	Yield
Stage #1: bendamustine With thionyl chloride In dichloromethane for 1h; Reflux; Stage #2: 13-(2-amino)ethoxymatrine With potassium carbonate In chloroform for 22h; Reflux;	51%

bendamustine (16506-27-7) + 1,3,5-tris(3-aminopropyl)benzene → 1,3,5-tris{3-{{4-[6-bis(2-chloroethyl)amino-3-methylbenzo[d]imidazol-2-yl]butanoyl}amino}propyl}benzene

Conditions	Yield
Stage #1: bendamustine With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane; N,N-dimethyl-formamide at -20 - 20℃; Stage #2: 1,3,5-tris(3-aminopropyl)benzene With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at -20 - 20℃; for 20h;	42%

hydroxymethylparthenolide (93930-15-5) + bendamustine (16506-27-7) → ((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-5-yl)methyl 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide at 20℃;	40%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 4h;	39.7%

4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl methyl(2-(methylamino)ethyl)carbamate trifluoroacetate + bendamustine (16506-27-7) → 4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl (2-(4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-methylbutanamido)ethyl)(methyl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	38%

C20H34N4O6 (1297582-72-9) + bendamustine (16506-27-7) → C52H72Cl4N10O8

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 25h; Steglich reaction;	35%

sophora acid ethyl ester (109905-27-3) + bendamustine (16506-27-7) → C33H49Cl2N5O3

Conditions	Yield
Stage #1: bendamustine With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 0.25h; Stage #2: sophora acid ethyl ester With dmap In tetrahydrofuran at 20℃; for 48h;	32%

C18H30N4O6 (1297582-69-4) + bendamustine (16506-27-7) → C50H68Cl4N10O8

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 25h; Steglich reaction;	23.73%

diazomethane (186581-53-3, 908094-01-9) + bendamustine (16506-27-7) → 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid methyl ester (109882-25-9)

Conditions	Yield
In methanol

1-(2-hydroxyethyl)-1H-pyrrole-2,5-dione (1585-90-6) + bendamustine (16506-27-7) → C22H28N4O6 (1247136-75-9) + C22H27ClN4O5 (1247136-74-8) + 4-<1-Methyl-5-benzimidazolyl-(2)>butansaeure (109882-30-6) + 4-[5-[(2-chloroethyl)-(2-hydroxy-ethyl)amino]-1-methyl-benzimidazo-2-yl]-butanoic acid (109882-27-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 25 h / 20 °C 2: water / 8 h / 37 °C View Scheme

bendamustine (16506-27-7) → 4-<1-Methyl-5-benzimidazolyl-(2)>butansaeure (109882-30-6)

Conditions	Yield
With water at 37℃; for 2h; pH=7.4; aq. phosphate buffer;

bendamustine (16506-27-7) → 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanal (1376614-94-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: borane-THF / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 0 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C View Scheme

Upstream product

• 97832-05-8 4-{5-[bis(2-chloro-ethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid hydrochloride 
• 3543-73-5 ethyl 4‐(5‐amino‐1‐methyl‐1H‐benzo[d]imidazol‐2‐yl)butanoate 
• 3543-74-6 4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester 
• 3543-72-4 4‐(1‐methyl‐5‐nitro‐1H‐benzoimidazol‐2‐yl)butyric acid ethyl ester 
• 31349-48-1 4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid 
• 108-55-4 glutaric anhydride, 
• 369-36-8 6-fluoro-3-nitroaniline 
• 3543-75-7 bendamustine hydrochloride 

Downstream Products

• 109882-25-9 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid methyl ester 
• 109882-30-6 4-<1-Methyl-5-benzimidazolyl-(2)>butansaeure 
• 109882-27-1 4-[5-[(2-chloroethyl)-(2-hydroxy-ethyl)amino]-1-methyl-benzimidazo-2-yl]-butanoic acid 
• 1247136-75-9 C₂₂H₂₈N₄O₆ 
• 1247136-74-8 C₂₂H₂₇ClN₄O₅ 

Related news

Prospective observational study in comorbid patients with chronic lymphocytic leukemia receiving first-line Bendamustine (cas 16506-27-7) with rituximab08/09/2019

Chemoimmunotherapy with bendamustine and rituximab is an alternative treatment for elderly patients with CLL. The aim of this observational multicenter study was to prospectively assess efficacy and safety of bendamustine and rituximab in front-line therapy in patients with CLL and significant c...detailed

Simultaneous determination of Bendamustine (cas 16506-27-7) and γ-hydroxyBendamustine (cas 16506-27-7) in mice dried blood spots and its application in a mice pharmacokinetic study08/08/2019

A selective, sensitive and rapid mice dried blood spot (DBS) method has been developed and validated for the simultaneous quantification of bendamustine (BM) and γ-hydroxy-bendamustine (HBM) as per regulatory guidelines using an LC-MS/MS. Quality control, calibration curve and study sample DBS ...detailed

Relevant articles and documents

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)

Hydrolysis products of the cancerostatic drug Cytostasan (Bendamustin)

-