Alternatived Products of [ 3543-74-6 ]
Product Details of [ 3543-74-6 ]
| CAS No. : | 3543-74-6 |
MDL No. : | MFCD09840918 |
| Formula : |
C18H27N3O4
|
Boiling Point : |
- |
| Linear Structure Formula : | - |
InChI Key : | SJYOJVBTSZGDQH-UHFFFAOYSA-N |
| M.W : |
349.42
|
Pubchem ID : | 13086945 |
| Synonyms : |
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Chemical Name : | Ethyl 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate |
Safety of [ 3543-74-6 ]
| Signal Word: | Warning |
Class: | N/A |
| Precautionary Statements: | P280-P305+P351+P338 |
UN#: | N/A |
| Hazard Statements: | H302 |
Packing Group: | N/A |
| GHS Pictogram: |
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Application In Synthesis of [ 3543-74-6 ]
* 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.
- Downstream synthetic route of [ 3543-74-6 ]
- 1
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[ 3543-74-6 ]
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[ 3543-75-7 ]
| Yield | Reaction Conditions | Operation in experiment |
| 76.2% |
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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. |
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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. |
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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%. |
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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. |
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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%). |
Reference：
[1]Patent: US2014/31560,2014,A1 .Location in patent: Paragraph 0113; 0114; 0115; 0116; 0117; 0118
[2]Patent: WO2012/106117,2012,A1 .Location in patent: Page/Page column 11
[3]Patent: CN105693620,2016,A .Location in patent: Paragraph 0135; 0136; 0137; 0138; 0139; 0140; 0141
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