ChemicalBook CAS DataBase List Bendamustine hydrochloride

Bendamustine hydrochloride synthesis

13synthesis methods

Product Name:Bendamustine hydrochloride
CAS Number:3543-75-7
Molecular formula:C16H22Cl3N3O2
Molecular Weight:394.72

5-[Bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazole-2-butanoic acid ethyl ester

3543-74-6

3543-75-7

Example 9 Synthesis of 4-[5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoic acid (9, bendamustine hydrochloride hydrate) 1. 250 g (0.7154 mol) of ethyl 5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzimidazole-2-butanoate (compound 7) was dissolved in 2000 ml of dichloromethane and cooled to -1 °C. 212 g (1.78 mol) of thionyl chloride was slowly added dropwise over 30 min, controlling the reaction temperature to not exceed -1 °C. After the dropwise addition was completed, the reaction mixture was continued to be stirred at -1 °C for 30 min, then gradually warmed up to room temperature and stirred for 16 hours. 2. The solvent and excess thionyl chloride were removed by vacuum distillation to afford the hydrochloride salt of compound 8. To the residue, 2.6 kg of 37% hydrochloric acid and 1.4 L of water were added, heated to 75 °C and kept for 30-40 minutes for the hydrolysis reaction of the ester. Subsequently, 25 g of activated carbon was added and stirred at 75°C for 10 minutes, filtered and the filtrate was concentrated in vacuum. 3. The concentrated residue was dissolved in 1000 ml of water, heated to 55 °C and then cooled to 50 °C, then further cooled to -2 °C and kept for 30 min to promote crystallization. The crude product (9) was collected by filtration, washed sequentially with 250 g of water and 200 g of acetone, and dried under vacuum at 35 °C for 2 h. 245 g (0.5936 mol, 83% yield) of the crude product was obtained, with a water content of 4.5%. 4. 245 g of the crude product (9) was dissolved in 330 g of 37% hydrochloric acid, 1.28 kg of water (ca. 35 °C) and 650 g of acetone (ca. 35 °C) were added and stirred for 10 min. 0.5g of bendamustine hydrochloride hydrate was added as a crystalline seed, and the mixture was cooled to -20°C over a period of 2 hours and held at this temperature for 90 minutes. The precipitate was filtered and washed first with a mixture of 120 g of water and 90 g of acetone and then with 275 g of acetone. 5. The purified bendamustine hydrochloride hydrate was dried under vacuum at 35°C for about 2 hours to give 225 g (0.545 mol, 76.2% yield) of pure product (>99.8% content). The water content can be adjusted to about 1% by vacuum drying at 50°C (theoretical water content of 4.4% for the single hydrate).

3543-74-6 Synthesis

3543-74-6
201 suppliers
$25.00/250mg

3543-75-7
397 suppliers
$35.00/10 mg

Yield:3543-75-7 76.2%

Reaction Conditions:

Stage #1:4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester with thionyl chloride in dichloromethane at -1 - 22; for 17 h;
Stage #2: with hydrogenchloride in water at 75;

Steps:

9 Example 9: Synthesis of 4-[5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoic acid (9, Bendamustine hydrochloride hydrate)
Example 9
Synthesis of 4-[5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoic acid (9, Bendamustine hydrochloride hydrate)
250 g (0.7154 mol) compound (7) was dissolved in 2000 ml methylene chloride and 212 g (1.78 mol) thionyl chloride added at -1° C. within a period of 30 minutes.
Thereby the temperature rose briefly to ca. 4° C.
Following addition the reaction solution was stirred for a further 30 minutes at -1° C.
The solution was then stirred for ca. 16 h at ca. 22° C.
Thereafter the solvent and excess thionyl chloride were removed by distillation under vacuum.
To hydrolyse the ester the remaining residue (compound 8 as its hydrochloride) was treated with 2.6 kg 37% hydrochloric acid and 1.4 l water, heated to ca.
75° C. and held at this temperature for 30-40 minutes. 25 g activated carbon was then added and stirred for 10 minutes at 75° C.
The solution was filtered and concentrated under vacuum.
To crystallise crude compound (9) the residue was dissolved in 1000 ml water at ca.
55° C., the solution cooled to ca.
-2° C. and then held at this temperature for ca. 30 minutes.
The crude product (9) was filtered off, washed with 250 g water and 200 g acetone and dried for 2 h at ca. 35° C. under vacuum.
The yield of crude compound (9) was 245 g (0.5936 mol) and had a water content of 4.5% (83% of theory). 245 g compound (9) were dissolved in 330 g 37% hydrochloric acid at ca. 40° C., treated with 1.28 kg water (temperature ca. 35° C.) and 650 g acetone (temperature ca. 35° C.) and stirred for 10 minutes. Crystallisation was initiated by the addition of 0.5 g Bendamustine hydrochloride hydrate, the mixture cooled within a period of 2 h to ca. -20° C. and then held at this temperature for ca. 90 minutes. The precipitate was filtered under suction. The crystals were washed initially with a mixture of 120 g water and 90 g acetone and subsequently with 275 g acetone. The pure Bendamustine hydrochloride hydrate was dried for ca. 2 h at ca. 35° C. under vacuum. Thus 225 g (0.545 mol) of pure (>99.8% content) compound (9) was obtained with an overall yield of 76.2% for this step. Through drying of the Bendamustine hydrochloride hydrate under vacuum at ca. 50° C. the water content could be adjusted to ca. 1% in contrast to 4.4% of the mono hydrates.

References:

Heyl Chemisch-pharmazeutische Fabrik GmbH & Co. KG;Frey, Michael;Walther, Dirk-Detlef US2014/31560, 2014, A1 Location in patent:Paragraph 0113; 0114; 0115; 0116; 0117; 0118

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109882-25-9 Synthesis