* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With sodium acetate trihydrate In water; acetic acid at 0 - 25℃; for 23 h; Stage #2: With potassium carbonate In dichloromethane at 20 - 25℃;
Example-5 Preparation of Ethyl 4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III) Ethyl 4-[5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (II, 200.0 g, 0.763 mol) was added to DM Water (1.1 L). Aqueous sodium acetate.3H2O (20.0 g sodium acetate.3H2O in 100 mL DM water) and acetic acid (400 mL) was added and agitated till complete dissolution of compound of the formula II. The reaction mixture was cooled to 0-5° C. and ethylene oxide (270.0 g, 6.12 mole) was added maintaining the temperature of the reaction mixture at 0-5° C. The reaction mixture was stirred at 0-5° C. for 5 hours. The temperature of reaction mixture was raised to 20-25° C. and agitated at 20-25° C. for 18 hours. After completion of the reaction, dichloromethane (2.0 L) was added at 20-25° C. followed by addition of aqueous solution of potassium carbonate (440.0 g potassium carbonate in 1.1 L DM water) portion wise at 20-25° C. to control the evaluation of effervescence and agitated at 20-25° C. for 5-10 minutes. The layers were separated. The organic layer (dichloromethane) was washed with DM water (1.0 L) twice and organic layer was concentrated under vacuum at 40-50° C. till viscous mass is obtained. The viscous mass was dissolved in acetone (1.0 L), cooled to 0-5° C. and agitated at 0-5° C. for 1 hour. The solid separated out was filtered, washed with chilled (0-5° C.) acetone (200.0 mL) and dried at 40-50° C. under vacuum for 6 hours to give the title compound (III, 210.0 g; 78.53percent), with a purity of 99.06percent.
With calcium carbonate In acetonitrile at 80 - 90℃;
Example-1 Preparation of Ethyl 4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III) Ethyl 4-[5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (II, 40.0 g, 0.153 mol) was added to 2-bromoethanol (80 mL) and agitated for 15-30 minutes. Acetonitrile (80 mL) and calcium carbonate (61.3 g, 0.61 mol) were added to the reaction mixture. The reaction mixture was heated to 80-90° C. within 2 hours and refluxed at 80-90° C. for 34-38 hours. The reaction mixture was cooled to below 70° C. and acetonitrile (80.0 mL) was added. The reaction mixture was further cooled to 20-30° C. and filtered through celite prewashed with acetonitrile. The filtrate was concentrated at 50-60° C. under vacuum till viscous mass is obtained. The viscous mass was cooled to 20-30° C. Dichloromethane (320.0 mL) was added to the viscous mass under stirring and washed with potassium carbonate solution (32.0 g in 200 mL water). The organic layer was washed with DM water twice. The organic layer (Dichloromethane) was concentrated under vacuum at 35-40° C. till viscous mass is attained. The viscous mass was dried under vacuum at 35-40° C. for one hour. Ethyl acetate (160.0 mL) was added to the viscous mass and cooled to 0-5° C. and stirred for one hour. The solid separated out was filtered and washed with ethyl acetate. The isolated solid was dissolved in dichloromethane and concentrated the solution under vacuum at 35-40° C. till viscous mass. The viscous mass was dissolved in acetone and cooled to 0-5° C. under stirring. The solid separated out was filtered, washed with acetone and dried at 40-45° C. under vacuum for 4-6 hours to give the title compound (III, 30.1 g; 56.30percent), with a purity of 97.22percent.
343.5 g
With potassium carbonate In water at 69 - 70℃; for 13.5 h; Large scale
[0079] To a solution of 81.3 g (650.6 mmol) 2-bromoethanol, 1 g potassium iodide and 100 g water was added 17.0g (65 mmol) compound (6). The reaction mixture was heated to 65-70 °C and held at this temperature for 8 h to 12 h.The pH value of the solution was held between 4.2-5.5 during this period by dropwise addition of a solution of 20.0 g(151.4 mmol) diammonium hydrogen phosphate in 35 g water. The control of pH over the duration of the reaction waseffected through use of a pH electrode. The conversion was followed by HPLC. The reaction was continued until thefraction of compound (7A) was ≤ 1.5 percent. Thereby ca. 8percent of compound (7B) had formed and the proportion of compound(7) was ca. 87percent. The reaction mixture was subsequently concentrated to dryness at ca. 55-60 °C under vacuum. Tothe residue was added 150 g water and, preferably with an alkali metal carbonate, the pH value adjusted to ca. 8.5. Thedesired product (7) was extracted with 200 g methylene chloride or 225 g chloroform, and the organic phase subsequentlywashed with 60 - 80 g water. The organic phase was then concentrated to dryness and the remaining oil or alreadycrystalline residue dissolved in 200 g ethyl acetate or alternatively in 60 g actetonitrile. Compound (7) crystallised at ca.5 °C and was filtered under suction, washed with 20 g cold ethyl acetate or alternatively with 15 g cold acetonitrile anddried at 60 -70 °C. The yield of compound (7) was 18.3 g (52.4 mmol) with a content of ≥ 98.2percent (80.5 percent of theory). Thecrude product contained ≤0.6percent compound (7A) and compound (7B) respectively as well as <0.15percent of compound (7C).0082] Analogous to Example 4 but with use of 9.0 g (65 mmol) potassium carbonate dissolved in 12 g water to holdthe pH value between 4.2 - 5.5. Identical results in terms of yield and quality.[0084] This example is a scaled-up analogue of Example 6 with use of 340 g (1.3 mol) compound (6), 2000 ml waterand 1625 g (13 mol) 2-bromoethanol. The reaction was performed without potassium iodide at 69 - 70°C.. The pH valuewas held between 4.2 - 5.5 using a solution of 138 g sodium carbonate (1.3 mol) in 500 g water. Until a content ofcompound (7A) of ≤1.5percent was reached, the duration of the reaction was 13.5 h. The yield of compound (7) was 365 gcrude and 343.5 g after recrystallisation from acetonitrile (75.6percent of theory).
17.2 g
With diammonium phosphate; potassium iodide In water at 65 - 70℃;
To a solution of 81.3 g (650.6 mmol) 2-bromoethanol, 1 g potassium iodide and 100 g water was added 17.0 g (65 mmol) compound (6). The reaction mixture was heated to 65-70° C. and held at this temperature for 8 h to 12 h. The pH value of the solution was held between 4.2-5.5 during this period by dropwise addition of a solution of 20.0 g (151.4 mmol) diammonium hydrogen phosphate in 35 g water. The control of pH over the duration of the reaction was effected through use of a pH electrode. The conversion was followed by HPLC. The reaction was continued until the fraction of compound (7A) was ≦1.5percent. Thereby ca. 8percent of compound (7B) had formed and the proportion of compound (7) was ca. 87percent. The reaction mixture was subsequently concentrated to dryness at ca. 55-60° C. under vacuum. To the residue was added 150 g water and, preferably with an alkali metal carbonate, the pH value adjusted to ca. 8.5. The desired product (7) was extracted with 200 g methylene chloride or 225 g chloroform, and the organic phase subsequently washed with 60-80 g water. The organic phase was then concentrated to dryness and the remaining oil or already crystalline residue dissolved in 200 g ethyl acetate or alternatively in 60 g acetonitrile. Compound (7) crystallised at ca. 5° C. and was filtered under suction, washed with 20 g cold ethyl acetate or alternatively with 15 g cold acetonitrile and dried at 60-70° C. The yield of compound (7) was 18.3 g (52.4 mmol) with a content of ≧98.2percent (80.5percent of theory). The crude contained ≦0.6percent compound ( 7A) and compound (7B) respectively as well as <0.15percent of compound (7C). The crude product obtained was recrystallized from ethyl acetate, or alternatively from acetonitrile, toluene, propan-2-ol, tetrahydrofuran, acetone, isopopyl acetate or water, prior to further conversion to compound ( 8). Thereby the yield of compound (7) was 17.2 g (94.0percent recrystallization yield) with a content of >99.2percent, wherein compound (7A) was removed below a content of 0.2percent and compound (7B) below 0.3percent. Through the course of the reaction, the content of compound (7C) was kept below 0.15percent, as this compound can only poorly be removed by recrystallization from the above described solvents. The overall yield of this step was 76.5percent of theory and was thus ca. 12.5percent higher than that described in the procedure using ethylene oxide as according to DD34727 and ca. 31percent higher in comparison to the favoured procedure of WO2011079193 involving addition of Hünig's base.
With sodium acetate; acetic acid In water at 0 - 25℃; for 23 h;
Example-5 Preparation of Ethyl 4-{5-[bis(2-hydroxyethyI)amino]-l-methyl-lH-benzimidazol- 2-yl} butanoate (III) Ethyl 4-[5-amino-l -methyl- l H-benzimidazol-2-yl)butanoate (II, 200.0g, 0.763mol) was added to DM Water (1.1L). Aqueous sodium acetate.3H20 (20.0g sodium acetate.3H20 in lOOmL DM water) and acetic acid (400mL) was added and agitated till complete dissolution of compound of the formula II. The reaction mixture was cooled to 0-5°C and ethylene oxide (270. Og, 6.12mole) was added maintaining the temperature of the reaction mixture at 0-5°C. The reaction mixture was stirred at 0-5°C for 5 hours. The temperature of reaction mixture was raised to 20-25°C and agitated at 20-25°C for 18 hours. After completion of the reaction, dichloromethane (2.0L) was added at 20-25°C followed by addition of aqueous solution of potassium carbonate (440. Og potassium carbonate in 1.1L DM water) portion wise at 20-25°C to control the evaluation of effervescence and agitated at 20-25°C for 5-10 minutes. The layers were separated. The organic layer (dichloromethane) was washed with DM water (1.0L) twice and organic layer was concentrated under vacuum at 40-50°C till viscous mass is obtained. The viscous mass was dissolved in acetone (1.0L), cooled to 0-5°C and agitated at 0-5°C for 1 hour. The solid separated out was filtered, washed with chilled (0-5°C) acetone (200.0mL) and dried at 40-50°C under vacuum for 6 hours to give the title compound (III, 210.0g; 78.53percent), with a purity of 99.06percent.
Example 1 Preparation of 1H-Benzimidazol-1-Methyl-5-N,N-di(2-Hydroxyethyl)-2-Butanoic Acid Ethyl Ester 1H-Benzimidazol-1-methyl-5-amino-2-butanoic acid (50 gm), water (285 ml) and acetic acid (80 ml) were added at room temperature. The solution was then cooled to 0 to 5° C. under stirring and ethylene oxide gas was passed in the reaction till the reaction mixture weight increases to 60 gm. The reaction mass was maintained for 1 hour at 0 to 5° C. and then temperature allowed to room temperature. The reaction mass was maintained for 30 hours at room temperature and then added water (2000 ml) and dichloromethane (2000 ml). To the reaction mass was added sodium bicarbonate (230 gm) and then the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layers were combined and the solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added hexane (400 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration, washed with cyclohexane and then dried at 35 to 40° C. for 2 hours 30 minutes to obtain 63 gm of 1H-benzimidazol-1-methyl-5-N,N-di(2-hydroxyethyl)-2-butanoic acid ethyl ester.
EXAMPLE-II Preparation of Ethyl 4-(5-(bis(2-Hydroxyethyl)Amino)-1-Methyl-1H-Benzo[d]-Imidazol-2-yl)Butanoate (Formula-IV) To a clean dry flask were charged compound of formula III (20 g), sodium carbonate (16.24 g), sodium Iodide (10.6 g) and 80 ml of 2-chloroethanol. The mixture was stirred for 5 minutes at room temperature and the reaction mass was heated to 65-70° C. and maintained for 8-12 hours. The mass was cooled to room temperature and pH adjusted to 1.0 using 6N HCl. The aqueous layer was extracted with ethyl acetate and the aqueous layer pH is adjusted to 8 to 9 using sodium carbonate solution. The Aqueous layer is extracted with dichloromethane and is distilled out completely and the solid obtained which is then purified in ethyl acetate to give 10 g of the title compound.
Stage #1: With thionyl chloride In dichloromethane at -1 - 22℃; for 17 h; Stage #2: With hydrogenchloride In water at 75℃;
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 37percent 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 4.5percent (83percent of theory). 245 g compound (9) were dissolved in 330 g 37percent 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 (>99.8percent content) compound (9) was obtained with an overall yield of 76.2percent for this step. Through drying of the Bendamustine hydrochloride hydrate under vacuum at ca. 50° C. the water content could be adjusted to ca. 1percent in contrast to 4.4percent of the mono hydrates.
75%
Stage #1: With thionyl chloride In chloroform at 0 - 5℃; Stage #2: With hydrogenchloride; pyrographite In water at 30℃; Reflux
HBI-ethylbutyrate (molecular weight = 349.42 g/mol) was dissolved in CHCI3 (10 x mass of HBI-ethylbutyrate). The solution was cooled to about 0 - 5 °C and thionyl chloride (molecular weight = 118.96 g/mol, 2.11 equivalents) was added over 1 - 2 hours. After stirring for an additional 0.25 - 1 hour, the mixture was warmed to 25 +/- 5 °C and stirred for an additional 20 - 24 hours. Aqueous hydrochloride acid (32percent, 2.8 x mass of HBI-ethylbutyrate) was added and the organic phase was removed. The aqueous phase was degassed at 30 °C for 15 - 30 minutes at 100-200 mbar). A suspension of active charcoal (0.02 x mass of HBI ethylbutyrate) in aqueous hydrochloric acid (0.2 x mass of HBI ethylbutyrate) was added to the aqueous phase. The mixture was heated to 85 - 90 °C within 1 hour and stirred for 4 - 5 hours at reflux. After cooling, the suspension was filtered and rinsed with aqueous hydrochloric acid (0.2 x mass of HBI ethylbutyrate). The solvent was distilled under reduced pressure at an inner temperature of<= 65 °C. About seventy percent (+/-5percent) of the total hydrochloric acid was distilled off. Warm (35-40 °C) water (4x mass of HBI ethylbutyrate) was added. Seeding may be necessary if no crystallization occurs within 30 minutes. After crystallization, the thick suspension is cooled to about 15 - 25 °C and stirred for 1 - 2 hours or overnight at<= 15 - 25 °C. The product is filtered, washed three times with water (0 - 5 °C, total water = 4 x mass of HBI ethylbutyrate) and at least three times with acetone (0 - 5 °C, total acetone = 4 x mass of HBI ethylbutyrate). The washed product was treated at least 4 times with acetone (2 x mass of HBI ethylbutyrate) at reflux for at least 1 hour. The hot suspension was filtered and the solid dried at<= 35 - 40 °C. Yield = 75 +/- 15percent bendamustine hydrochloride.
54 g
Stage #1: With thionyl chloride In dichloromethane at 0 - 45℃; for 1.75 h; Stage #2: With hydrogenchloride In water at 80 - 90℃; for 3 h;
Example 2 Preparation of Bendamustine Hydrochloride To a solution of 1H-benzimidazol-1-methyl-5-N,N-di(2-hydroxyethyl)-2-butanoic acid ethyl ester (63 gm) as obtained in example 1 in dichloromethane (630 ml) was added thionyl chloride (50.4 gm) for 15 minutes at 0 to 5° C. The contents were heated to 35 to 45° C. and then maintained for 2 hours 30 minutes. To the reaction mixture was added dichloromethane (1000 ml) and then the layers were separated. The aqueous layer was extracted with dichloromethane and combined the organic layers. The organic layer was treated with charcoal (5percent, 5 gm) and the solvent was ,distilled off under vacuum to obtain a residual mass. The residual mass was dissolved in concentrated hydrochloric acid (630 ml) and then heated to 80 to 90° C. The reaction mass was maintained for 3 hours at 80 to 90° C. and the solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added water (125 ml), stirred for 20 minutes and filtered. The solid obtained was dried to give 54 gm of bendamustine hydrochloride.
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.
75%
HBI-ethylbutyrate (molecular weight = 349.42 g/mol) was dissolved in CHCI3 (10 x mass of HBI-ethylbutyrate). The solution was cooled to about 0 - 5 C and thionyl chloride (molecular weight = 118.96 g/mol, 2.11 equivalents) was added over 1 - 2 hours. After stirring for an additional 0.25 - 1 hour, the mixture was warmed to 25 +/- 5 C and stirred for an additional 20 - 24 hours. Aqueous hydrochloride acid (32%, 2.8 x mass of HBI-ethylbutyrate) was added and the organic phase was removed. The aqueous phase was degassed at 30 C for 15 - 30 minutes at 100-200 mbar). A suspension of active charcoal (0.02 x mass of HBI ethylbutyrate) in aqueous hydrochloric acid (0.2 x mass of HBI ethylbutyrate) was added to the aqueous phase. The mixture was heated to 85 - 90 C within 1 hour and stirred for 4 - 5 hours at reflux. After cooling, the suspension was filtered and rinsed with aqueous hydrochloric acid (0.2 x mass of HBI ethylbutyrate). The solvent was distilled under reduced pressure at an inner temperature of? 65 C. About seventy percent (+/-5%) of the total hydrochloric acid was distilled off. Warm (35-40 C) water (4x mass of HBI ethylbutyrate) was added. Seeding may be necessary if no crystallization occurs within 30 minutes. After crystallization, the thick suspension is cooled to about 15 - 25 C and stirred for 1 - 2 hours or overnight at? 15 - 25 C. The product is filtered, washed three times with water (0 - 5 C, total water = 4 x mass of HBI ethylbutyrate) and at least three times with acetone (0 - 5 C, total acetone = 4 x mass of HBI ethylbutyrate). The washed product was treated at least 4 times with acetone (2 x mass of HBI ethylbutyrate) at reflux for at least 1 hour. The hot suspension was filtered and the solid dried at? 35 - 40 C. Yield = 75 +/- 15% bendamustine hydrochloride.
Example 20: Preparation of crude Bendamustine hydrochloride (form B) [00103] A 5 L bottle was charged with 197 g of phosphorus oxychloride. The contents of the bottle were heated to 50 0C and 150 g of ethyl 4-{5-[bis(2- hydroxycthyl)amino]-l -methyl- lH-benzimidazol-2-yl}butanoatc("BBOH") dissolved in 600 ml of dichloromethane was added. Reaction mixture was stirred at 75-85 0C for 4-5 hours. The reaction mixture was then cooled to room temperature and diluted with 450 ml dichloromethane to form a solution. Then the solution was decomposed with 900 ml of 21 % hydrochloric acid and then this reaction mixture was heated at 92 - 96 C for 5-6 h. The resulting solution was then cooled, and its pH was adjusted with 50 % sodium hydroxide to a pH of 1.4 - 1.6 at 0 - 200C. The product crystallized and the mixture was stirred 30 - 60 minutes at 0-100C. The crude Bendamustine was separated by filtration and the filter cake was washed three times with 600 ml of cold dilute hydrochloric acid (1 :20), then three times with 600 ml of cold water, and then three times with 600 ml of ethyl acetate . The filter cake was then dried in wet (relative humidity over 30 %) nitrogen to give 144 g of crude bendamustine hydrochloride.
Example 2:Preparation of bendamustine hydrochlorideTo a solution of lH-benzimidazol-l-methyl-5-N,N-di(2-hydroxyethyl)-2-butanoic acid ethyl ester (63 gm) as obtained in example 1 in dichloromethane (630 ml) was added thionyl chloride (50.4 gm) for 15 minutes at 0 to 5C. The contents were heated to 35 to 45C and then maintained for 2 hours 30 minutes. To the reaction mixture was added dichloromethane (1000 ml) and then the layers were separated. The aqueous layer was extracted with dichloromethane and combined the organic layers. The organic layer was treated with charcoal (5%, 5 gm) and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was dissolved in concentrated hydrochloric acid (630 ml) and then heated to 80 to 90C. The reaction mass was maintained for 3 hours at 80 to 90 C and the solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added water (125 ml), stirred for 20 minutes and filtered. The solid obtained was dried to give 54 gm of bendamustine hydrochloride.Chromatographic purity of bendamustine hydrochloride: 99.2%; andContent of 4-(7,8-dihydro-6-(2-chloroethylamino)-3-methyl-l,4-thiazino[3,2- g]benzimidazoyl(2))-butyric acid impurity: 0.5%.
EXAMPLE-III Preparation of Bendamustine Hydrochloride (Formula-I) To a compound of formula IV (10 g) in dichloromethane (100 ml), thionyl chloride (20 ml) is charged slowly at 0-5 C. and then allowed to reflux. The reaction is distilled to dryness and then 100 ml conc. HCl is charged to the reaction. The temperature is raised to 80-90 C. and maintained for 6-8 h. The mass is treated with activated carbon, filtered and distilled to give the title product, which is washed with acetone (100 ml).
54 g
Example 2 Preparation of Bendamustine Hydrochloride To a solution of 1H-benzimidazol-1-methyl-5-N,N-di(2-hydroxyethyl)-2-butanoic acid ethyl ester (63 gm) as obtained in example 1 in dichloromethane (630 ml) was added thionyl chloride (50.4 gm) for 15 minutes at 0 to 5 C. The contents were heated to 35 to 45 C. and then maintained for 2 hours 30 minutes. To the reaction mixture was added dichloromethane (1000 ml) and then the layers were separated. The aqueous layer was extracted with dichloromethane and combined the organic layers. The organic layer was treated with charcoal (5%, 5 gm) and the solvent was ,distilled off under vacuum to obtain a residual mass. The residual mass was dissolved in concentrated hydrochloric acid (630 ml) and then heated to 80 to 90 C. The reaction mass was maintained for 3 hours at 80 to 90 C. and the solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added water (125 ml), stirred for 20 minutes and filtered. The solid obtained was dried to give 54 gm of bendamustine hydrochloride.
Preparation of Bendamustine Hydrochloride (Crude) (0099) Step 1: 4-{5-[Bis-(2-hydroxy-ethyl)-amino]-1-methyl-1H-benzoimidazol-2-yl}-butyric acid ethyl ester (27.0 kg) was dissolved in 270 kg chloroform. After cooling to 0 to 5 C., 19.2 kg thionyl chloride was added over about 1 hour. The mixture was warmed to 25 C.±5 C. and stirred for 20 to 24 hours. 75.6 kg hydrochloric acid (32% aqueous solution) was then added. After phase separation, the organic (lower) phase was removed. The product remained in the aqueous phase. (0100) Step 2: A suspension of activated charcoal in hydrochloric acid was added to the aqueous phase obtained in step 1. The mixture was heated over 1 hour to 85 to 90 C. and stirred for 4 to 5 hours at reflux. The suspension was then filtered and rinsed with aqueous hydrochloric acid. The solvent was distilled off under reduced pressure at a temperature not exceeding 65 C. 108 kg to 324 kg (108 kg preferred) of warm (35 to 45 C.) deionized water was added to induce crystallization. (0101) After crystallization, the mixture was cooled to 20 C±5 C. and stirred for an additional 1 to 2 hours or overnight. The product was collected by filtration on a filter dryer, washed with three portions each of 108 to 324 kg (108 kg preferred) deionized water and 108 to 216 kg (108 kg preferred) of cold acetone. The crude product was treated four times each with 54 to 108 kg (54 kg preferred) acetone at reflux for at least 1 hour, in the filter dryer. The suspension was filtered and the product dried at a temperature not higher than 40 C. under reduced pressure, to give 21.4 kg±2.1 kg bendamustine hydrochloride crude (70%±10%, calculated as dried substance). (0102) Step 3 (optional): The product obtained from step 2 was dissolved in hydrochloric acid (32% aqueous solution) and heated to reflux (85 to 90 C.) for at least 4 hours. To improve color, activated charcoal can be added to the hydrochloric acid and the mixture heated to reflux (85 to 90 C.) for at least 4 hours. With activated charcoal, the suspension was filtered and rinsed with aqueous hydrochloric acid. Solvent was distilled off under reduced pressure at a temperature not exceeding 65 C. The mixture was then diluted with deionized water. If no crystallization occurred within 15 min, the mixture was seeded. After crystallization, the suspension was stirred at 40 C.±5 C. for one hour, then cooled to 20 C.±5 C. After stirring an additional 1 to 2 hours at 20 C.±5 C., the product was collected by filtration, washed three times with cold deionized water, and at least three times with cold acetone. The crude product was treated four times with acetone at reflux for at least 1 hour. The suspension was filtered and the product dried at a temperature not higher than 40 C., under reduced pressure. Yield was of crude bendamustine hydrochloride was 80%±10%. Preparation of Purified Bendamustine Hydrochloride (0103) Bendamustine HCl crude (15.0 kg) was suspended with 0.45 kg activated charcoal in ethanol/water (vol/vol=97/3) at room temperature. The mixture was quickly warmed to 75 to 80 C. and stirred for not more than 10 min under reflux conditions. The mixture was filtered to remove the activated charcoal. After filtration, 33.0 kg of filtered acetone was added quickly at 40-50 C. to induce crystallization. (0104) After crystallization, the mixture was stirred for 30 to 60 min at 40-50 C., then cooled to 0 to 5 C., and stirred for at least an additional 30 min or overnight. The product was collected by filtration and washed with three 45 kg of cold acetone. After that, the crude product was treated 4 times each with 30 kg acetone at reflux for at least 1 hour. The suspension was filtered and the product dried at a temperature not higher than 40 C. under reduced pressure providing 11.3±1.5 kg bendamustine hydrochloride (75%±10%).
With sodium carbonate; sodium iodide; at 20 - 70℃;
To a clean dry flask were charged compound of formula III (20 g), sodium carbonate (16.24 g), sodium Iodide (10.6 g) and 80 ml of 2-chloroethanol. The mixture was stirred for 5 minutes at room temperature and the reaction mass was heated to 65-70 C and maintained for 8-12 hours. The mass was cooled to room temperature and pH adjusted to 1.0 using 6N HCI. The aqueous layer was extracted with ethyl acetate and the aqueous layer pH is adjusted to 8 to 9 using sodium carbonate solution. The Aqueous layer is extracted with dichloromethane and is distilled out completely and the solid obtained which is then purified in ethyl acetate to give 10 g of the title compound.
10 g
With sodium carbonate; sodium iodide; at 65 - 70℃;
EXAMPLE-II Preparation of Ethyl 4-(5-(bis(2-Hydroxyethyl)Amino)-1-Methyl-1H-Benzo[d]-Imidazol-2-yl)Butanoate (Formula-IV) To a clean dry flask were charged compound of formula III (20 g), sodium carbonate (16.24 g), sodium Iodide (10.6 g) and 80 ml of 2-chloroethanol. The mixture was stirred for 5 minutes at room temperature and the reaction mass was heated to 65-70 C. and maintained for 8-12 hours. The mass was cooled to room temperature and pH adjusted to 1.0 using 6N HCl. The aqueous layer was extracted with ethyl acetate and the aqueous layer pH is adjusted to 8 to 9 using sodium carbonate solution. The Aqueous layer is extracted with dichloromethane and is distilled out completely and the solid obtained which is then purified in ethyl acetate to give 10 g of the title compound.
To a compound of formula IV (10 g) in dichloromethane (100 ml), thionyl chloride (20 ml) is charged slowly at 0-5 C and then allowed to reflux. The reaction is distilled to dryness and then 100 ml cone. HCI is charged to the reaction. The temperature is raised to 80-90 C and maintained for 6-8 h. The mass is treated with activated carbon, filtered and distilled to give the title product, which is washed with acetone (100 ml).
With thionyl chloride; In dichloromethane; at -1 - 22℃; for 17h;
[0085] 250 g (0.7154 mol) compound (7) was dissolved in 2000 ml methylene chloride and 212 g (1.78 mol) thionylchloride added at -1 C within a period of 30 minutes. Thereby the temperature rose briefly to ca. 4 C. Following additionthe 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 esterthe remaining residue (compound 8 as its hydrochloride) was treated with 2.6 kg 37% hydrochloric acid and 1.4 I water,heated to ca. 75 C and held at this temperature for 30 -40 minutes. 25 g activated carbon was then added and stirredfor 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 temperaturefor ca. 30 minutes. The crude product (9) was filtered off, washed with 250 g water and 200 g acetone and dried for 2h at ca. 35 C under vacuum.[0086] The yield of crude compound (9) was 245 g (0.5936 mol) and had a water content of 4.5 % (83% of theory).[0087] 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 wasinitiated 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.[0088] The precipitate was filtered under suction. The crystals were washed initially with a mixture of 120 g water and90 g acetone and subsequently with 275 g acetone.[0089] The pure Bendamustine hydrochloride hydrate was dried for ca. 2 h at ca. 35C 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.[0090] Through drying of the Bendamustine hydrochloride hydrate under vacuum at ca. 50 C the water content couldbe adjusted to ca. 1 % in contrast to 4.4% of the mono hydrates.
4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Example 1aProduction of Bendamustine Ethyl Ester26.7 g oxalyl chloride (1.6 equivalents) was dissolved in 279 ml dichloromethane and cooled to 1 C. At 1 C. a mixture of 17 ml dimethylformamide (DMF) and 50 ml dry dichloromethane was added slowly. A solution of 23 g ethyl-4-(5-(bis-(2-hydroxyethyl)-amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate in 115 ml dichloromethane was added to the resulting reaction mixture. The reaction mixture was stirred for 8 hr with recycling (45 C. jacket temperature), cooled and then mixed with 50 ml ultra-pure water. Through the addition of 25% K2CO3 solution, the pH value was adjusted to pH 8-9.5. After intensive thorough mixing, the organic phase was separated and the aqueous phase was extracted with additional 83 ml dichloromethane. The combined organic phases were dried in a vacuum until reaching weight constancy.This experiment was carried out six times. The following yields of bendamustine ethyl ester were obtained:
With trichlorophosphate; for 0.25h;Reflux;
a) Ethyl Ester of Bendamustine A 500 mL three-necked round bottom flask equipped with a magnetic stirring bar, internal thermometer and a reflux-condenser with oil ventile was charged with phosphorus oxychloride (134 g, 80.0 mL, 874 mmol) and heated to an internal temperature of about 60-70 C. <strong>[3543-74-6]4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}-butanoic acid ethyl ester</strong> (40 g, 114 mmol) was added in portions. After the addition was completed the mixture was heated to reflux temperature and stirring was continued for a further 15 min. The mixture was allowed to reach room temperature and 1,2-dimethoxyethane (90 mL) was added with stirring (solution 1). A 2000 mL three-necked round bottom flask was charged with potassium bicarbonate (412.1 g, 4115 mmol) and potable water (525 mL). Solution 1 was added slowly with stirring, maintaining an internal temperature of about 20 to 30 C., after which stirring was continued for a further 60 min. The resulting solid was isolated, washed with water (4*100 mL) and used without further purification. The product may optionally be dried in vacuum at temperatures of not more than 40 C. Yield (moist): 89.26 g; calculated dry: 46.3 g, >100%; product usually contains residual water even after drying. 1H NMR (600 MHz, DMSO-d6, ppm): delta=7.73 (d, 3J=8.8 Hz, 1H, arom. R2NCCH=CH), 6.92 (d, 4J=2.3 Hz, 1H, arom. R2NCCH), 6.78 (dd, 3J=8.8 Hz, 4J=2.3 Hz, 1H, arom. R2NCCH=CH), 4.04 (q, 3J=7.1 Hz, 2H, OCH2CH3), 3.70 (s, 8H, CH2CH2Cl), 3.65 (s, 3H, CH3N), 2.92 (t, 3J=7.4 Hz, 2H, CH2-CH2-CH2-COOEt), 2.44 (t, 3J=7.3 Hz, 2H, CH2-CH2-CH2-COOEt), 2.00 (m, 2H, CH2-CH2-CH2-COOEt). 13C-{H}-NMR (150 MHz, DMSO-d6, ppm): delta=172.7 (COOEt), 154.4 (arom.), 143.4 (arom.), 142.3 (arom.), 129.3 (arom.), 110.2 (arom.), 110.0 (arom.), 102.3 (arom.), 59.8 (CH2CH3), 53.6 (2*CH2Cl), 41.5 (2*CH2N), 32.9 (CH2), 29.4 (CH3), 25.7 (CH2), 22.2 (CH2), 14.2 (CH2CH3). LC-MS (ESI+): m/z=386.2 (M+H+; 100% relative Intensity)
With thionyl chloride; In dichloromethane; for 6h;Reflux;
Example-2 Preparation of Ethyl 4-{5-[bis(2-chloroethyl)amino]-l-methyl-lH-benzimidazol-2- yl}butanoate (IV) 4-{5-[bis(2-hydroxyethyl)amino]-l-methyl-lH-benzimidazol-2-yl}butanoate (III, 90.0g, 1.15 mole) was added to dichloromethane (6.24L) and agitated till clear solution is formed. A solution of thionyl chloride (292.3g, 2.52 mol) in dichloromethane (1.56L) was added slowly in 2 to 3 hours. After complete addition of thionyl chloride solution, reaction mixture was refluxed at 35-45C for 6 hours. The reaction mixture was cooled to 20-30C and 1.95L dichloromethane was added. Potassium carbonate solution (351.0g in 1.95L water) was added to the reaction mixture slowly to control the evaluation of effervescence. The layers were separated. The organic (dichloromethane) layer was washed with brine solution. The organic layer was concentrated at 30-35C under vacuum till viscous mass is obtained. The viscous mass was dissolved in acetone (1.95L) and DM water (1.365L) was slowly. The resulting mixture was stirred at 20-30C for one hour followed by cooling to 0-5C. The solid separated out was washed with chilled mixture of acetone (390mL) and DM water (195.5mL) twice. The material was sucked dried to dryness and used as such for next step.
Example-2 Preparation of Ethyl 4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (IV) 4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III, 90.0 g, 1.15 mole) was added to dichloromethane (6.24 L) and agitated till clear solution is formed. A solution of thionyl chloride (292.3 g, 2.52 mol) in dichloromethane (1.56 L) was added slowly in 2 to 3 hours. After complete addition of thionyl chloride solution, reaction mixture was refluxed at 35-45 C. for 6 hours. The reaction mixture was cooled to 20-30 C. and 1.95 L dichloromethane was added. Potassium carbonate solution (351.0 g in 1.95 L water) was added to the reaction mixture slowly to control the evaluation of effervescence. The layers were separated. The organic (dichloromethane) layer was washed with brine solution. The organic layer was concentrated at 30-35 C. under vacuum till viscous mass is obtained. The viscous mass was dissolved in acetone (1.95 L) and DM water (1.365 L) was slowly. The resulting mixture was stirred at 20-30 C. for one hour followed by cooling to 0-5 C. The solid separated out was washed with chilled mixture of acetone (390 mL) and DM water (195.5 mL) twice. The material was sucked dried to dryness and used as such for next step.
Example-5 Preparation of Ethyl 4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III) Ethyl 4-[5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (II, 200.0 g, 0.763 mol) was added to DM Water (1.1 L). Aqueous sodium acetate.3H2O (20.0 g sodium acetate.3H2O in 100 mL DM water) and acetic acid (400 mL) was added and agitated till complete dissolution of compound of the formula II. The reaction mixture was cooled to 0-5 C. and ethylene oxide (270.0 g, 6.12 mole) was added maintaining the temperature of the reaction mixture at 0-5 C. The reaction mixture was stirred at 0-5 C. for 5 hours. The temperature of reaction mixture was raised to 20-25 C. and agitated at 20-25 C. for 18 hours. After completion of the reaction, dichloromethane (2.0 L) was added at 20-25 C. followed by addition of aqueous solution of potassium carbonate (440.0 g potassium carbonate in 1.1 L DM water) portion wise at 20-25 C. to control the evaluation of effervescence and agitated at 20-25 C. for 5-10 minutes. The layers were separated. The organic layer (dichloromethane) was washed with DM water (1.0 L) twice and organic layer was concentrated under vacuum at 40-50 C. till viscous mass is obtained. The viscous mass was dissolved in acetone (1.0 L), cooled to 0-5 C. and agitated at 0-5 C. for 1 hour. The solid separated out was filtered, washed with chilled (0-5 C.) acetone (200.0 mL) and dried at 40-50 C. under vacuum for 6 hours to give the title compound (III, 210.0 g; 78.53%), with a purity of 99.06%.
Example 1 :Preparation of lH-benzimidazol-l-methyI-5-N,N-di(2-hydroxyethyl)-2-butanoic acid ethyl esterlH-Benzimidazol-l-methyl-5-amino-2-butanoic acid (50 gm), water (285 ml) and acetic acid (80 ml) were added at room temperature. The solution was then cooled to 0 to 5C under stirring and ethylene oxide gas was passed in the reaction till the reaction mixture weight increases to 60 gm. The reaction mass was maintained for 1 hour at 0 to 5C and then temperature allowed to room temperature. The reaction mass was maintained for 30 hours at room temperature and then added water (2000 ml) and dichloromethane (2000 ml). To the reaction mass was added sodium bicarbonate (230 gm) and then the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layers were combined and the solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added hexane (400 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration, washed with cyclohexane and then dried at 35 to 40C for 2 hours 30 minutes to obtain 63 gm of lH-benzimidazol-l-methyl-5-N,N-di(2-hydroxyethyl)-2-butanoic acid ethyl ester.
With sodium acetate; acetic acid; In water; at 0 - 25℃; for 23h;
Example-5 Preparation of Ethyl 4-{5-[bis(2-hydroxyethyI)amino]-l-methyl-lH-benzimidazol- 2-yl} butanoate (III) Ethyl 4-[5-amino-l -methyl- l H-benzimidazol-2-yl)butanoate (II, 200.0g, 0.763mol) was added to DM Water (1.1L). Aqueous sodium acetate.3H20 (20.0g sodium acetate.3H20 in lOOmL DM water) and acetic acid (400mL) was added and agitated till complete dissolution of compound of the formula II. The reaction mixture was cooled to 0-5C and ethylene oxide (270. Og, 6.12mole) was added maintaining the temperature of the reaction mixture at 0-5C. The reaction mixture was stirred at 0-5C for 5 hours. The temperature of reaction mixture was raised to 20-25C and agitated at 20-25C for 18 hours. After completion of the reaction, dichloromethane (2.0L) was added at 20-25C followed by addition of aqueous solution of potassium carbonate (440. Og potassium carbonate in 1.1L DM water) portion wise at 20-25C to control the evaluation of effervescence and agitated at 20-25C for 5-10 minutes. The layers were separated. The organic layer (dichloromethane) was washed with DM water (1.0L) twice and organic layer was concentrated under vacuum at 40-50C till viscous mass is obtained. The viscous mass was dissolved in acetone (1.0L), cooled to 0-5C and agitated at 0-5C for 1 hour. The solid separated out was filtered, washed with chilled (0-5C) acetone (200.0mL) and dried at 40-50C under vacuum for 6 hours to give the title compound (III, 210.0g; 78.53%), with a purity of 99.06%.
With hydrogenchloride; In water; at 60℃; for 2.5h;pH Ca. 2;
A 5 ml round-bottomed vial equipped with a magnetic stirring bar and a stopper was charged with the compound of formula (12) (244 mg) and 0.437 ml of 39.5 weight % aqueous solution of methylamine. The mixture was stirred at 70C for 4.5 hours and cooled to room temperature. The mixture was diluted with 5 ml of ethanol and transferred into a 25 ml pressure reactor equipped with a magnetic stirring bar. The reactor was charged with 136 mg of Pd/C catalyst (3.9 %), flushed with nitrogen, and pressurized with hydrogen to 60 psi. The mixture was stirred at 23C at 50-60 psi of hydrogen for 2 hours. The reactor was flushed with nitrogen and charged, under stirring, with 357 mg of glutaric acid anhydride in portions within 5 hours. The catalyst was filtered off. The filtrate was acidified with 35% HC1 to a pH of about 2 and heated to 60C for 2.5 hours to produce a solution comprising 90% of the compound of formula (11) (R = ethyl).
With calcium carbonate; In acetonitrile; at 80 - 90℃;
Example-1 Preparation of Ethyl 4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III) Ethyl 4-[5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (II, 40.0 g, 0.153 mol) was added to 2-bromoethanol (80 mL) and agitated for 15-30 minutes. Acetonitrile (80 mL) and calcium carbonate (61.3 g, 0.61 mol) were added to the reaction mixture. The reaction mixture was heated to 80-90 C. within 2 hours and refluxed at 80-90 C. for 34-38 hours. The reaction mixture was cooled to below 70 C. and acetonitrile (80.0 mL) was added. The reaction mixture was further cooled to 20-30 C. and filtered through celite prewashed with acetonitrile. The filtrate was concentrated at 50-60 C. under vacuum till viscous mass is obtained. The viscous mass was cooled to 20-30 C. Dichloromethane (320.0 mL) was added to the viscous mass under stirring and washed with potassium carbonate solution (32.0 g in 200 mL water). The organic layer was washed with DM water twice. The organic layer (Dichloromethane) was concentrated under vacuum at 35-40 C. till viscous mass is attained. The viscous mass was dried under vacuum at 35-40 C. for one hour. Ethyl acetate (160.0 mL) was added to the viscous mass and cooled to 0-5 C. and stirred for one hour. The solid separated out was filtered and washed with ethyl acetate. The isolated solid was dissolved in dichloromethane and concentrated the solution under vacuum at 35-40 C. till viscous mass. The viscous mass was dissolved in acetone and cooled to 0-5 C. under stirring. The solid separated out was filtered, washed with acetone and dried at 40-45 C. under vacuum for 4-6 hours to give the title compound (III, 30.1 g; 56.30%), with a purity of 97.22%.
343.5 g
With potassium carbonate; In water; at 69 - 70℃; for 13.5h;pH 4.2 - 5.5;Large scale;
[0079] To a solution of 81.3 g (650.6 mmol) 2-bromoethanol, 1 g potassium iodide and 100 g water was added 17.0g (65 mmol) compound (6). The reaction mixture was heated to 65-70 C and held at this temperature for 8 h to 12 h.The pH value of the solution was held between 4.2-5.5 during this period by dropwise addition of a solution of 20.0 g(151.4 mmol) diammonium hydrogen phosphate in 35 g water. The control of pH over the duration of the reaction waseffected through use of a pH electrode. The conversion was followed by HPLC. The reaction was continued until thefraction of compound (7A) was ? 1.5 %. Thereby ca. 8% of compound (7B) had formed and the proportion of compound(7) was ca. 87%. The reaction mixture was subsequently concentrated to dryness at ca. 55-60 C under vacuum. Tothe residue was added 150 g water and, preferably with an alkali metal carbonate, the pH value adjusted to ca. 8.5. Thedesired product (7) was extracted with 200 g methylene chloride or 225 g chloroform, and the organic phase subsequentlywashed with 60 - 80 g water. The organic phase was then concentrated to dryness and the remaining oil or alreadycrystalline residue dissolved in 200 g ethyl acetate or alternatively in 60 g actetonitrile. Compound (7) crystallised at ca.5 C and was filtered under suction, washed with 20 g cold ethyl acetate or alternatively with 15 g cold acetonitrile anddried at 60 -70 C. The yield of compound (7) was 18.3 g (52.4 mmol) with a content of ? 98.2% (80.5 % of theory). Thecrude product contained ?0.6% compound (7A) and compound (7B) respectively as well as <0.15% of compound (7C).0082] Analogous to Example 4 but with use of 9.0 g (65 mmol) potassium carbonate dissolved in 12 g water to holdthe pH value between 4.2 - 5.5. Identical results in terms of yield and quality.[0084] This example is a scaled-up analogue of Example 6 with use of 340 g (1.3 mol) compound (6), 2000 ml waterand 1625 g (13 mol) 2-bromoethanol. The reaction was performed without potassium iodide at 69 - 70C.. The pH valuewas held between 4.2 - 5.5 using a solution of 138 g sodium carbonate (1.3 mol) in 500 g water. Until a content ofcompound (7A) of ?1.5% was reached, the duration of the reaction was 13.5 h. The yield of compound (7) was 365 gcrude and 343.5 g after recrystallisation from acetonitrile (75.6% of theory).
17.2 g
With diammonium phosphate; potassium iodide; In water; at 65 - 70℃;pH 4.2 - 5.5;
To a solution of 81.3 g (650.6 mmol) 2-bromoethanol, 1 g potassium iodide and 100 g water was added 17.0 g (65 mmol) compound (6). The reaction mixture was heated to 65-70 C. and held at this temperature for 8 h to 12 h. The pH value of the solution was held between 4.2-5.5 during this period by dropwise addition of a solution of 20.0 g (151.4 mmol) diammonium hydrogen phosphate in 35 g water. The control of pH over the duration of the reaction was effected through use of a pH electrode. The conversion was followed by HPLC. The reaction was continued until the fraction of compound (7A) was ?1.5%. Thereby ca. 8% of compound (7B) had formed and the proportion of compound (7) was ca. 87%. The reaction mixture was subsequently concentrated to dryness at ca. 55-60 C. under vacuum. To the residue was added 150 g water and, preferably with an alkali metal carbonate, the pH value adjusted to ca. 8.5. The desired product (7) was extracted with 200 g methylene chloride or 225 g chloroform, and the organic phase subsequently washed with 60-80 g water. The organic phase was then concentrated to dryness and the remaining oil or already crystalline residue dissolved in 200 g ethyl acetate or alternatively in 60 g acetonitrile. Compound (7) crystallised at ca. 5 C. and was filtered under suction, washed with 20 g cold ethyl acetate or alternatively with 15 g cold acetonitrile and dried at 60-70 C. The yield of compound (7) was 18.3 g (52.4 mmol) with a content of ?98.2% (80.5% of theory). The crude contained ?0.6% compound ( 7A) and compound (7B) respectively as well as <0.15% of compound (7C). The crude product obtained was recrystallized from ethyl acetate, or alternatively from acetonitrile, toluene, propan-2-ol, tetrahydrofuran, acetone, isopopyl acetate or water, prior to further conversion to compound ( 8). Thereby the yield of compound (7) was 17.2 g (94.0% recrystallization yield) with a content of >99.2%, wherein compound (7A) was removed below a content of 0.2% and compound (7B) below 0.3%. Through the course of the reaction, the content of compound (7C) was kept below 0.15%, as this compound can only poorly be removed by recrystallization from the above described solvents. The overall yield of this step was 76.5% of theory and was thus ca. 12.5% higher than that described in the procedure using ethylene oxide as according to DD34727 and ca. 31% higher in comparison to the favoured procedure of WO2011079193 involving addition of Huenig's base.
With thionyl chloride; In dichloromethane; at 5 - 20℃; for 16h;
Example 12 Synthesis of 4-[5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoic acid (9, Bendamustine) To a solution of compound (7) (5.00 g, 14 mmol) in 40 ml methylene chloride thionyl chloride (4.26 g, 36 mmol) is added at 5 C. Afterwards, the solution is stirred at ambient temperature for 16 h. The solvent is removed by distillation under vacuum. To the thereby produced brown oil 45 ml of 37% hydrochloric acid and 30 ml water is added and heated to 95 C. for 30 min. Subsequently 0.9 g activated carbon is added and stirred for 10 minutes at 95 C. The product is filtered and concentrated under vacuum until a dried product is formed. Afterwards a crystallisation of compound (9) is carried out in 20 ml water. The product was filtered, washed with water and acetone and dried under vacuum for 2 h at 50 C. The yield of compound (9) amounts to 4.3 g (11 mmol) with a content >99% (73% of theory).
With diammonium hydrogenphosphate; In water; at 65 - 70℃;pH 4.2 - 5.5;
[0079] To a solution of 81.3 g (650.6 mmol) 2-bromoethanol, 1 g potassium iodide and 100 g water was added 17.0g (65 mmol) compound (6). The reaction mixture was heated to 65-70 C and held at this temperature for 8 h to 12 h.The pH value of the solution was held between 4.2-5.5 during this period by dropwise addition of a solution of 20.0 g(151.4 mmol) diammonium hydrogen phosphate in 35 g water. The control of pH over the duration of the reaction waseffected through use of a pH electrode. The conversion was followed by HPLC. The reaction was continued until thefraction of compound (7A) was ? 1.5 %. Thereby ca. 8% of compound (7B) had formed and the proportion of compound(7) was ca. 87%. The reaction mixture was subsequently concentrated to dryness at ca. 55-60 C under vacuum. Tothe residue was added 150 g water and, preferably with an alkali metal carbonate, the pH value adjusted to ca. 8.5. Thedesired product (7) was extracted with 200 g methylene chloride or 225 g chloroform, and the organic phase subsequentlywashed with 60 - 80 g water. The organic phase was then concentrated to dryness and the remaining oil or alreadycrystalline residue dissolved in 200 g ethyl acetate or alternatively in 60 g actetonitrile. Compound (7) crystallised at ca.5 C and was filtered under suction, washed with 20 g cold ethyl acetate or alternatively with 15 g cold acetonitrile anddried at 60 -70 C. The yield of compound (7) was 18.3 g (52.4 mmol) with a content of ? 98.2% (80.5 % of theory). Thecrude product contained ?0.6% compound (7A) and compound (7B) respectively as well as 99.2%, wherein compound (7A)was removed below a content of 0.2 % and compound (7B) below 0.3 %. Through the course of the reaction, the contentof compound (7C) was kept below 0.15 %, as this compound can only poorly be removed by recrystallization from theabove described solvents. The overall yield of this step was 76.5% of theory and was thus ca. 12.5% higher than thatdescribed in the procedure using ethylene oxide as according to DD34727 and ca. 31% higher in comparison to thefavoured procedure of W02011079193 involving addition of Huenig?s base.Example 5: Synthesis of ethyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-
Example 1 Preparation of 1H-Benzimidazol-1-Methyl-5-N,N-di(2-Hydroxyethyl)-2-Butanoic Acid Ethyl Ester 1H-Benzimidazol-1-methyl-5-amino-2-butanoic acid (50 gm), water (285 ml) and acetic acid (80 ml) were added at room temperature. The solution was then cooled to 0 to 5 C. under stirring and ethylene oxide gas was passed in the reaction till the reaction mixture weight increases to 60 gm. The reaction mass was maintained for 1 hour at 0 to 5 C. and then temperature allowed to room temperature. The reaction mass was maintained for 30 hours at room temperature and then added water (2000 ml) and dichloromethane (2000 ml). To the reaction mass was added sodium bicarbonate (230 gm) and then the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layers were combined and the solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added hexane (400 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration, washed with cyclohexane and then dried at 35 to 40 C. for 2 hours 30 minutes to obtain 63 gm of 1H-benzimidazol-1-methyl-5-N,N-di(2-hydroxyethyl)-2-butanoic acid ethyl ester.
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